Article

Antitumor effects of α-bisabolol against pancreatic cancer

August 2011
Cancer Science 102(12):2199-205

DOI: 10.1111/j.1349-7006.2011.02082.x

Source
PubMed

Authors:

In the present study, we investigated whether α-bisabolol, a sesquiterpene alcohol present in essential oils derived from a variety of plants, has antitumor effects against pancreatic cancer. α-Bisabolol induced a decrease in cell proliferation and viability in pancreatic cancer cell lines (KLM1, KP4, Panc1, MIA Paca2), but not in pancreatic epithelial cells (ACBRI515). α-Bisabolol treatment induced apoptosis and suppressed Akt activation in pancreatic cancer cell lines. Furthermore, α-bisabolol treatment induced the overexpression of early growth response-1 (EGR1), whereas EGR1 siRNA decreased the α-bisabolol-induced cell death of KLM1 cells. Tumor growth in both subcutaneous and peritoneal xenograft nude mouse models was significantly inhibited by intragastric administration of 1000 mg/kg of α-bisabolol, once a week for three weeks. The results indicate that α-bisabolol could be a novel therapeutic option for the treatment of pancreatic cancer.

α-Bisabolol Attenuates Doxorubicin Induced Renal Toxicity by Modulating NF-κB/MAPK Signaling and Caspase-Dependent Apoptosis in Rats

Article

Full-text available

Sep 2022
INT J MOL SCI

Doxorubicin (DOX) is a well-known and effective antineoplastic agent of the anthracycline family. But, multiple organ toxicities compromise its invaluable therapeutic usage. Among many toxicity types, nephrotoxicity is one of the major concerns. In recent years many approaches, including bioactive agents of natural origin, have been explored to provide protective effects against chemotherapy-related complications. α-Bisabolol is a naturally occurring monocyclic sesquiterpene alcohol identified in the essential oils of various aromatic plants and possesses a wide range of pharmacological properties such as antioxidant, anti-inflammatory, analgesic, cardioprotective, antibiotic, anti-irritant, and anticancer activities. The present study aimed to evaluate the effects of α-Bisabolol on DOX-induced nephrotoxicity in Wistar male albino rats. Nephrotoxicity was induced in rats by injecting a single dose of DOX (12.5 mg/kg, i.p.), and the test compound, α-Bisabolol (25 mg/kg) was administered intraperitoneally along with DOX as a co-treatment daily for 5 days. DOX-injected rats showed reduction in body weight along with a concomitant fall in antioxidants and increased lipid peroxidation in the kidney. DOX-injection also increased levels/expressions of proinflammatory cytokines namely tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) and inflammatory mediators like inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and activated nuclear factor kappa-B (NF-κB)/mitogen-activated protein kinases (MAPK) signaling in the kidney tissues. DOX also triggered apoptotic cell death, evidenced by the increased expression of pro-apoptotic markers like BCL2-Associated X Protein (Bax), cleaved caspase-3, caspase- 9, and cytochrome-C) and a decrease in the expressions of anti-apoptotic markers namely B-cell lymphoma 2 (Bcl2) and B-cell lymphoma-extra large (Bcl-xL) in the kidney. These biochemical alterations were additionally supported by light microscopic findings, which revealed structural alterations in the kidney. However, treatment with α-Bisabolol prevented body weight loss, restored antioxidants, mitigated lipid peroxidation, and inhibited the rise in proinflammatory cytokines, as well as favorably modulated the expressions of NF-κB/MAPK signaling and apoptosis markers in DOX-induced nephrotoxicity. Based on the results observed, it can be concluded that α-Bisabolol has potential to attenuate DOX-induced nephrotoxicity by inhibiting oxidative stress and inflammation mediated activation of NF-κB/MAPK signaling alongwith intrinsic pathway of apoptosis in rats. The study findings are suggestive of protective potential of α-Bisabolol in DOX associated nephrotoxicity and this could be potentially useful in minimizing the adverse effects of DOX and may be a potential agent or adjuvant for renal protection.

α-Bisabolol improves 5-aminolevulinic acid retention in buccal tissues: Potential application in the photodynamic therapy of oral cancer

Article

Aug 2017

Context: 5-Aminolevulinic acid (5-ALA) is a prodrug used in photodynamic therapy (PDT) of tumors, including cancer of the oral mucosa. 5-ALA poorly penetrates oral tissues due to its high hydrophilicity, which impairs its local effects in PDT. Objectives: To examine whether α-bisabolol (α-Bis) influences the 5-ALA permeability in the porcine buccal mucosa, to an extent that improves its application in PDT (which requires low permeation and high retention in the buccal mucosa). Methods: In vitro permeability studies with 5-ALA (1% and 10% w/w) associated with α-Bis (1% to 20% w/w) in propylene glycol were carried out at 4h and 24h using porcine buccal mucosa in a modified Franz cell system. The in vitro release profiles (0.5 to 48h) of the selected formulation and its respective control were determined using artificial membranes. Samples of buccal mucosa treated with the formulation were submitted to histopathological analysis, using a routine optical microscopy technique. Results: The association of 1% 5-ALA and 5% α-Bis provided the best results; after 4h of treatment with this formulation, the 5-ALA permeation was low and its retention in the mucosa was six-fold higher than that promoted by the control formulation (5-ALA alone). Histological analysis of the porcine buccal mucosa evidenced that 5% α-Bis altered the tissue morphology, which probably promoted 5-ALA retention. We concluded that 5% α-Bis is a potential adjuvant in formulations containing 5-ALA that could improve its retention after topical oral administration for the PDT treatment of cancer.

The antineoplastic agent α-bisabolol promotes cell death by inducing pores in mitochondria and lysosomes

Article

Full-text available

Aug 2016
APOPTOSIS

The sesquiterpene α-bisabolol (α-BSB) has been shown to be an effective cytotoxic agent for a variety of human cancer cells in culture and animal models. However, much of its intracellular action remains elusive. We evaluated the cytotoxic action of α-BSB against CML-T1, Jurkat and HeLa cell lines, as preclinical models for myeloid, lymphoid and epithelial neoplasias. The approach included single cell analysis (flow cytometry, immunocytology) combined with cytotoxicity and proliferation assays to characterize organelle damage, autophagy, cytostatic effect, and apoptosis. The study focuses on the relevant steps in the cytotoxic cascade triggered by α-BSB: (1) the lipid rafts through which α-BSB enters the cells, (2) the opening of pores in the mitochondria and lysosomes, (3) the activation of both caspase-dependent and caspase-independent cell death pathways, (4) the induction of autophagy and (5) apoptosis. The effectiveness of α-BSB as an agent against tumor cells is grounded on its capability to act on different layers of cell regulation to elicit different concurrent death signals, thereby neutralizing a variety of aberrant survival mechanisms leading to treatment resistance in neoplastic cell.

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

Article

Full-text available

Jul 2020

In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review.

Chemical Composition and Biological Activity of the Essential Oil Isolated from the Leaves of Achillea fragrantissima Growing Wild in Yemen

Article

Full-text available

Sep 2019

α-Bisabolol Attenuates NF-κB/MAPK Signaling Activation and ER-Stress-Mediated Apoptosis by Invoking Nrf2-Mediated Antioxidant Defense Systems against Doxorubicin-Induced Testicular Toxicity in Rats

Article

Full-text available

Nov 2022

The present study investigated the effects of α-bisabolol on DOX-induced testicular damage in rats. Testicular damage was induced in rats by injecting DOX (12.5 mg/kg, i.p., single dose) into rats. α-Bisabolol (25 mg/kg, i.p.) was administered to the rats along with DOX pre- and co-treatment daily for a period of 5 days. DOX-injected rats showed a decrease in absolute testicular weight and relative testicular weight ratio along with concomitant changes in the levels/expression levels of oxidative stress markers and Nrf2 expression levels in the testis. DOX injection also triggered the activation of NF-κB/MAPK signaling and increased levels/expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and inflammatory mediators (iNOS and COX-2) in the testis. DOX triggered apoptosis, manifested by an increment in the expression levels of pro-apoptotic markers (Bax, Bcl2, cleaved caspase-3 and -9, and cytochrome-C) and a decline in the expression levels of anti-apoptotic markers (Bcl-xL and Bcl2) in the testis. Additionally, light microscopy revealed the changes in testicular architecture. α-Bisabolol rescued alterations in the testicular weight; restored all biochemical markers; modulated the expression levels of Nrf2-mediated antioxidant responses, NF-κB/MAPK signaling, endoplasmic reticulum (ER) stress, and apoptosis markers in DOX-injected testicular toxicity in rats. Based on our findings, it can be concluded that α-bisabolol has the potential to attenuate DOX-induced testicular injury by modifying NF-κB/MAPK signaling and the ER-stress-mediated mitochondrial pathway of apoptosis by invoking Nrf2-dependent antioxidant defense systems in rats. Based on the findings of the present study, α-bisabolol could be suggested for use as an agent or adjuvant with chemotherapeutic drugs to attenuate their deleterious effects of DOX on many organs including the testis. However, further regulatory toxicology and preclinical studies are necessary before making recommendations in clinical tests.

The Phytochemical Profile and Anticancer Activity of Anthemis tinctoria and Angelica sylvestris Used in Estonian Ethnomedicine

Article

Full-text available

Apr 2022

The aerial parts of Anthemis tinctoria L. and Angelica sylvestris L. and the roots of A. sylvestris have been used as traditional anticancer remedies in Estonian ethnomedicine. The aim of this study was to investigate content of essential oils (by gas chromatography) and polyphenolic compounds (using two different methods of high performance liquid chromatography–mass spectrometry (HPLC–MS)) of both plant species, as well as the in vitro anti-cancer effects of their essential oils and methanolic extracts. The average (n = 5 samples) yield of essential oils was 0.15%, 0.13%, and 0.17%, respectively. The principal compounds of the essential oil from the aerial parts of A. tinctoria were palmitic acid (15.3%), p-cymene (12.6%), and α-muurolene (12.5%), and α-pinene (45.4%), p-cymene (15.5%), and β-myrcene (13.3%) in aerial parts of A. sylvestris, while isocaryophyllene oxide (31.9%), α-bisabolol (17.5%), and α-pinene (12.4%) were the main constituents in the roots. The most abundant phenolic compounds in aerial parts were the derivatives of caffeic acid, quinic acid, and quercetin; the main compounds in roots of A. sylvestris were chlorogenic acid, quinic acid, and naringenin. The strongest anticancer effects were observed in essential oils of A. sylvestris roots and aerial parts on human carcinoma in the mouth cells (KB, IC50 19.73 μg/mL and 19.84 μg/mL, respectively). The essential oil of A. tinctoria showed a strong effect on KB and LNCaP cells (27.75–29.96 μg/mL). The methanolic extracts of both plants had no effect on the cancer cells studied.

The Nephroprotective Effects of α-Bisabolol in Cisplatin-Induced Acute Kidney Injury in Mice

Article

Full-text available

Apr 2022

Cisplatin (CP) treatment has been long associated with the development of acute kidney injury (AKI) through mechanisms involving inflammation and oxidative stress. α-Bisabolol (BIS), a sesquiterpene alcohol isolated from the essential oil of various plants, including chamomile, has garnered popularity lately due to its antioxidant, anti-inflammatory, and anticancer properties. Therefore, we investigated the nephroprotective effects of BIS in the murine model of CP-induced AKI and the underlying mechanism of action. BALB/c mice were given BIS orally at 25 mg/kg for 7 days. On day 7, they were given a single dose of CP at 20 mg/kg intraperitoneally. BIS treatment continued for 3 more days. The animals were sacrificed at the end of the experiment (day 11). Kidneys, plasma, and urine were collected, and subsequently, various physiological, biochemical, and histological parameters were assessed. BIS has significantly normalized the alterations of water intake, urine volume, relative kidney weight, and the concentrations of urea and creatinine, as well as the creatinine clearance induced by CP treatment. BIS significantly mitigated the effects of CP-induced kidney injury by reducing kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, adiponectin, and cystatin C. Likewise, the renal concentrations of proinflammatory cytokines, tumor necrosis factor α, interleukin (IL)-6 and IL-1β that were elevated in CP group were significantly reduced in mice treated with BIS and CP. A similar significant reduction was also observed in the CP-induced augmented levels of markers of oxidative stress, as well as the metabolite pteridine. Moreover, BIS significantly reduced the CP–induced renal DNA damage, and markedly lessened the acute tubular necrosis observed in kidney histology. Additionally, BIS significantly reduced the CP-induced increase in the phosphorylated nuclear factor κB (NFκB) in the kidney. These data strongly suggest that BIS exerts a protective action against CP-induced nephrotoxicity by mitigating inflammation and oxidative stress through the inhibition of NFκB activation. No overt adverse effects were noted with BIS treatment. Additional investigations should be done to consider BIS as an efficacious nephroprotective agent against CP.

Health Benefits, Pharmacological Effects, Molecular Mechanisms, and Therapeutic Potential of α-Bisabolol

Article

Full-text available

Mar 2022

α-Bisabolol is one of the important monocyclic sesquiterpenes, derived naturally from essential oils of many edible and ornamental plants. It was first obtained from Matricaria chamomilla, commonly known as chamomile or German chamomile. The available literature indicates that this plant along with other α-Bisabolol containing plants is popularly used in traditional medicine for potential health benefits and general wellbeing. Nutritional studies are indicative of the health benefits of α-Bisabolol. Numerous experimental studies demonstrated pharmacological properties of α-Bisabolol including anticancer, antinociceptive, neuroprotective, cardioprotective, and antimicrobial. This review aims to collectively present different pharmacological activities based on both in vitro and in vivo studies. In the present review using synoptic tables and figures, we comprehensively present that α-Bisabolol possesses therapeutic and protective activities, therefore, it can be used for potential health benefits based on pharmacological effects, underlying molecular mechanism, and favorable pharmaceutical properties. Based on the studies mostly performed in cell lines or animal models, it is evident that α-Bisabolol may be a promising nutraceutical and phytomedicine to target aberrant biological mechanisms which result in altered physiological processes and various ailments. Given the polypharmacological effects and pleiotropic properties, along with favorable pharmacokinetics, and dietary availability and safety, α-Bisabolol can be used as a dietary agent, nutraceutical or phytopharmaceutical agent or as an adjuvant with currently available modern medicines. The regulatory approval of this molecule for use as food additives, and in cosmetics and fragrance industry is also supportive of its human usage. Moreover, further studies are necessary to address pharmaceutical, pharmacological, and toxicological aspects before clinical or nutritional usage in humans. The pharmacological effects and biological actions opens up opportunities on the pharmacological basis of its use in future therapeutics.

Cannabis sativa Extract Induces Apoptosis in Human Pancreatic 3D Cancer Models: Importance of Major Antioxidant Molecules Present Therein

Article

Full-text available

Feb 2022
MOLECULES

In recent years, interest in Cannabis sativa L. has been rising, as legislation is moving in the right direction. This plant has been known and used for thousands of years for its many active ingredients that lead to various therapeutic effects (pain management, anti-inflammatory, antioxidant, etc.). In this report, our objective was to optimize a method for the extraction of cannabinoids from a clone of Cannabis sativa L. #138 resulting from an agronomic test (LaFleur, Angers, FR). Thus, we wished to identify compounds with anticancer activity on human pancreatic tumor cell lines. Three static maceration procedures, with different extraction parameters, were compared based on their median inhibitory concentration (IC50) values and cannabinoid extraction yield. As CBD emerged as the molecule responsible for inducing apoptosis in the human pancreatic cancer cell line, a CBD-rich cannabis strain remains attractive for therapeutic applications. Additionally, while gemcitabine, a gold standard drug in the treatment of pancreatic cancer, only triggers cell cycle arrest in G0/G1, CBD also activates the cell signaling cascade to lead to programmed cell death. Our results emphasize the potential of natural products issued from medicinal hemp for pancreatic cancer therapy, as they lead to an accumulation of intracellular superoxide ions, affect the mitochondrial membrane potential, induce G1 cell cycle arrest, and ultimately drive the pancreatic cancer cell to lethal apoptosis.

Mining methods and typical structural mechanisms of terpene cyclases

Article

Full-text available

Dec 2021

Terpenoids, formed by cyclization and/or permutation of isoprenes, are the most diverse and abundant class of natural products with a broad range of significant functions. One family of the critical enzymes involved in terpenoid biosynthesis is terpene cyclases (TCs), also known as terpene synthases (TSs), which are responsible for forming the ring structure as a backbone of functionally diverse terpenoids. With the recent advances in biotechnology, the researches on terpene cyclases have gradually shifted from the genomic mining of novel enzyme resources to the analysis of their structures and mechanisms. In this review, we summarize both the new methods for genomic mining and the structural mechanisms of some typical terpene cyclases, which are helpful for the discovery, engineering and application of more and new TCs.

Volatile oil of Teucrium alopecurus sensitizes colon cancer cells to TRAIL-induced cell death

Article

Full-text available

Jun 2021

TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), a member of cytokine family, is known to selectively induce apoptosis in cancer cells. However, developing resistance to TRAIL is a major obstacle in cancer therapy. In this study, the in vitro effect of Teucrium alopecurus (TA) essential oil on inhibition of cancer cell growth and enhancing TRAIL-induced apoptosis were investigated in colon cancer cells. Untreated tumor cell lines are used as controls. TA induced cell death and increased the anticancer effects of TRAIL as observed by cell toxicity, live/dead assay, cleavage of caspases and PARP. Furthermore, the mechanism of anticancer potentiating effect of TA was found to be linked with the upregulation of death receptors (DRs) and reduced expression of TRAIL decoy receptors (DcRs). TA also down-regulated antiapoptotic proteins and induced p53 in colon cancer cells. In addition, we observed upregulation of MAPK signalling pathway (p38 kinase, JNK, ERK) and increased expression of C/EBP homologous transcription factor (CHOP) and specificity protein 1 (SP1) by TA. These findings demonstrate the potent anticancer effect of bioactive constituents of Teucrium alopecurus essential oil.

Evaluation of DNA Damage on T47D Cell Lines Treated with Chloroform Extract of Agarwood (Gyrinops versteegii (Gilg.) Domke and Aquilaria malaccensis Lamk.) Leaves

Thesis

Jan 2021

Nur Ahmad Rudin

Breast cancer is the second most common cancer in the world after lung cancer and leading cause of death for women. DNA damage is a change in the basic structure of DNA that caused abnormal condition, change cell morphology, and increases the risk of cancer. One of the important indicators in cancer treatment is apoptosis. One of the hallmark of apoptosis is DNA fragmentation. The world of medicine paradigm tends to follow a lifestyle back to nature. Previous research has shown that agarwood leaves of Gyrinops versteegii and Aquilaria malaccensis have the potential to be developed as anticancer agents. Cytotoxicity assay on breast cancer T47D cell lines show IC50 value with moderate cytotoxic on mixed extract of agarwood leaves (141,47 μg/mL) and G. versteegii (152,84 μg/mL), and low cytotoxic on A. malaccensis (206,54 μg/mL). Therefore, this study aims to evaluate DNA damage in T47D cells with chloroform extract of agarwood leaves. Extraction was carried out with soxhletation method and chloroform solvent. Morphology cell, DNA fragmentation, and comet assay were carried out by treatment chloroform extract of agarwood leaves with concentration of 141,47 μg/mL (mixed extract), 152,84 μg/mL (G. versteegii), 206,54 μg/mL (A. malaccensis), 97,08 μg/mL (commercial herbs), and 0,39 μg/mL (Doxorubicin HCl) on T47D cell culture for (3, 6, and 48) hours. Data analysis was carried out qualitatively by number of DNA fragment and visually on cell morphology, and comet. Quantitative analysis was carried out by measuring DNA fragments and the level of DNA damage using Comet Score: Automatic Comet Assay Software 2.0.0.38 and Laptop Lenovo G410 RAM 8 GB Core I5. The results showed that chloroform extracts of A. malaccensis and G. versteegii were influence changing of membrane shrinkage and reduce of cell volume on cell morphology starts on 6 hours treatment and observed clearly at 48 hours treatment. Induction of DNA fragmentation started at 6 hours treatment time with 3 fragments and fragment size (800–2200) bp. The comet formation of T47D cells was started at 6 hours treatment with the category of DNA damage are mild to moderate. There is a correlation pattern between tail and head intensity, and is not related to area comets. The level of DNA damage obtained on the comet assay were in accordance with the number of fragments in DNA fragmentation.

A pharmacognostic approach for mitigating pancreatic cancer: emphasis on herbal extracts and phytoconstituents

Article

Full-text available

May 2021

Background Pancreatic cancer is studied as one of the most lethal cancers with currently no control of its lethality, mainly due to its late diagnosis and lack of foolproof treatment processes. Despite continuous efforts being made in looking for therapies to deal with cancer, it keeps on being a labyrinth for the researchers. Efforts like discovering new treatment options, repurposing existing drugs, are continuously made to deal with this cancer. Main body With the urge to get answers and the fact that nature has all roots of therapeutics, efforts are made in the direction of finding those answers for providing ministrations for pancreatic cancer from plant products. Plant products are used as treatment options either directly in the form of extracts or an alternative to them is individual phytochemicals that are either isolated from the plants or are commercially synthesized for various purposes. In this review, we put forward such pharmacognostic initiatives made in combating pancreatic cancer, focusing mainly on plant extracts and various phytochemicals; along with the mechanisms which they triggered to fulfill the need for cytotoxicity to pancreatic cancer cells (in vitro and in vivo). Conclusion This study will thus provide insights into new combination therapy that can be used and also give a clue on which plant product and phytoconstituent can be used in dealing with pancreatic cancer. Graphical abstract

Volatile Oil of Teucrium alopecurus sensitizes colon cancer cells to TRAIL-induced cell death

Article

Jun 2021

TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), a member of cytokine family, is known to selectively induce apoptosis in cancer cells. However, developing resistance to TRAIL is a major obstacle in cancer therapy. In this study, the in vitro effect of Teucrium alopecurus (TA) essential oil on inhibition of cancer cell growth and enhancing TRAIL-induced apoptosis were investigated in colon cancer cells. Untreated tumor cell lines are used as controls. TA induced cell death and increased the anticancer effects of TRAIL as observed by cell toxicity, live/dead assay, activation of caspases and cleavage of PARP. Furthermore, the mechanism of anticancer potentiating effect of TA was found to be associated with increased expression of death receptors (DRs) and reduced expression of TRAIL decoy receptors (DcRs). TA also down-regulated antiapoptotic proteins and induced p53 in colon cancer cells. In addition, we observed upregulation of MAPK signalling pathway (p38 kinase, JNK, ERK) and increased expression of C/EBP homologous transcription factor (CHOP) and specificity protein 1 (SP1) by TA. These findings demonstrate the potent anticancer effect of bioactive constituents of Teucrium alopecurus essential oil.

Sesquiterpenes and Their Derivatives-Natural Anticancer Compounds: An Update

Article

Aug 2020

Sesquiterpenes belongs to the largest group of plant secondary metabolites consisting of three isoprene building units. These compounds are widely distributed in various angiosperms, a few gymnosperms and bryophytes. Sesquiterpenes and their allied derivatives are bio-synthesized in various plant parts including leaves, fruits and roots. These plant-based metabolites are predominantly identified in the Asteraceae family, wherein up to 5000 complexes have been documented to date. Sesquiterpenes and their derivatives are characteristically associated with plant defence mechanisms owing to their antifungal, antibacterial and antiviral activities. Over the last two decades, these compounds have been reportedly demonstrated health promoting perspectives against a wide range of metabolic syndromes i.e. hyperglycemia, hyperlipidemia, cardiovascular complications, neural disorders, diabetes, and cancer. The high potential of sesquiterpenes and their derivatives against various cancers like breast, colon, bladder, pancreatic, prostate, cervical, brain, liver, blood, ovarium, bone, endometrial, oral, lung, eye, stomach and kidney are the object of this review. Predominantly, it recapitulates the literature elucidating sesquiterpenes and their derivatives while highlighting the mechanistic approaches associated with their potent anticancer activities such as modulating nuclear factor kappa (NF-kB) activity, inhibitory action against lipid peroxidation and retarding the production of reactive oxygen & nitrogen species (RO&NS).

Phytochemical analysis of agarwood (Gyrinops versteegii (Gilg.) Domke) leaves extracts as anticancer using GC-MS

Conference Paper

Dec 2019

Cancer is one of the main causes of death in the world. Indonesia’s natural wealth offers great potency for the development of cancer drugs, including Agarwood leaves Gyrinops versteegii (Gilg.) Domke. The previous study revealed that leaves extract of G. versteegii has cytotoxic activity on several cancer cell lines i.e. breast cancer (T47D), colon cancer (WiDr) and cervix cancer (HeLa). The limited study on the phytochemical content of G. versteegii due to the specific distribution of this species, only in the East part of Indonesia. This study aimed to analyze the phytochemical compounds of the leaves extract of G. versteegii and identified which were reported as anticancer according to the database. Samples were collected from the Bogor Botanical Gardens, West Java, Indonesia. Extraction was done by overnight maceration using chloroform and ethanol solvents in the ratio of sample: solvents at 1: 10 (w/v). Phytochemical content was analyzed using GC-MS (AOC-20i Shimadzu) equipped with auto- injector connected to an ESI mass spectrometer. The results showed that ethanol extract contained 21 compounds while chloroform extract 18 compounds. The most abundant compound detected in both extracts were fatty acid, namely palmitic acid, stearic acid, and pentadecanoic acid. Terpenoids observed as the second major compound in both extracts. Among the detected compounds, lauric acid, myristinic acid, palmitic acid, stearic acid, loliolide, phytol, farnesol, squalene, and nerolidol were observed in both extracts and reported as anticancer. Specific for the chloroform extract, oleic acid, globulol, bisabolol and 1- docosanol may responsible for the anticancer activity while in ethanol extract were digitoxin and nerol. This research is the first reported study on metabolite profiling of G. versteegii leaves extract. This result supports the further study on G. versteegii as the anticancer-resource plant.

Effects of Hexane Root Extract of Ferula hermonis Boiss. on Human Breast and Colon Cancer Cells An In Vitro and In Vivo Study

Article

Full-text available

Jul 2019
BMRI

Breast and colon cancers are leading causes of cancer-related deaths globally. Plants are a potential source of natural products that may be used for the treatment of cancer. Ferula hermonis (FH) is reported to have diverse therapeutic effects. However, there are few reports on the in vitro anticancer potential of FH extract. Our results showed that the Ferula hermonis root hexane extract (FHRH) can induce dose-dependent cytotoxic effects in breast and colon cancer cells with MTT IC 50 values of 18.2 and 25 í µí¼g/ml, respectively. The FHRH extract induced apoptosis in both breast and colon cancer cells; this was confirmed by light and nuclear staining, q-PCR, and caspase 3/7 activation. This study also demonstrated the antitumor activity of FHRH in 9,10-dimethylbenz[í µí»¼]anthracene DMBA-induced rodent mammary tumor model. The GC/MS analysis revealed the presence of 3,5-Dimethylbenzenemethanol, Alpha-Bisabolol, Alpha-pinene, Beta-pinene, and Baccatin III that have various pharmacological potentials. Overall, the present study suggests that FHRH extract possesses anticancer potential which is mediated through apoptotic effects in MDA-MB-231 and LoVo cells. The present study also considered a basis for further investigations into the potential use of FHRH extract as an anticancer therapy for breast and colon cancers.

The Effects of 2′,4′-Dihydroxy-6′-methoxy-3′,5′- dimethylchalcone from Cleistocalyx operculatus Buds on Human Pancreatic Cancer Cell Lines

Article

Full-text available

Jul 2019
MOLECULES

2′,4′-Dihydroxy-6’-methoxy-3′,5′-dimethylchalcone (DMC), a principal natural chalcone of Cleistocalyx operculatus buds, suppresses the growth of many types of cancer cells. However, the effects of this compound on pancreatic cancer cells have not been evaluated. In our experiments, we explored the effects of this chalcone on two human pancreatic cancer cell lines. A cell proliferation assay revealed that DMC exhibited concentration-dependent cytotoxicity against PANC-1 and MIA PACA2 cells, with IC50 values of 10.5 ± 0.8 and 12.2 ± 0.9 µM, respectively. Treatment of DMC led to the apoptosis of PANC-1 by caspase-3 activation as revealed by annexin-V/propidium iodide double-staining. Western blotting indicated that DMC induced proteolytic activation of caspase-3 and -9, degradation of caspase-3 substrate proteins (including poly[ADP-ribose] polymerase [PARP]), augmented bak protein level, while attenuating the expression of bcl-2 in PANC-1 cells. Taken together, our results provide experimental evidence to support that DMC may serve as a useful chemotherapeutic agent for control of human pancreatic cancer cells.

Antiparasitic effect of (−)-α-Bisabolol against Trypanosoma cruzi Y strain forms

Article

Jun 2019
DIAGN MICR INFEC DIS

Chagas disease is caused by Trypanosoma cruzi and affects about 7 million people worldwide. Benznidazole and nifurtimox have low efficacy and high toxicity. The present study was designed to identify the trypanocidal effect of (-)-α-Bisabolol (BIS) and investigate its mechanism. Epimastigotes and trypomastigotes were cultured with BIS and the viable cells were counted. BIS antiamastigote effect was evaluated using infected LLC-MK2 cells. MTT assay was performed to evaluate BIS cytotoxicity. Growth recovery was assessed to evaluate BIS effect after short times of exposure. BIS mechanism was investigated through flow cytometry, with 7-AAD and Annexin V-PE. DCFH-DA, rhodamine 123 (Rho123) and acridine orange (AO). Finally, enzymatic and computational assays were performed to identify BIS interaction with T. cruzi GAPDH (tcGAPDH). BIS showed an inhibitory effect on epimastigotes after all tested periods, as well on trypomastigotes. It caused cytotoxicity on LLC-MK2 cells at higher concentrations, with selectivity index (SeI) = 26.5. After treatment, infected cells showed a decrease in infected cells, the number of amastigotes per infected cell and the survival index (SuI). Growth recovery demonstrated that BIS effect causes rapid death of T. cruzi. Flow cytometry showed that BIS biological effect is associated with apoptosis induction, increase in cytoplasmic ROS and mitochondrial transmembrane potential, while reservosome swelling was observed at a late stage. Also, BIS action mechanism may be associated to tcGAPDH inhibition. Altogether, the results demonstrate that BIS causes cell death in Trypanosoma cruzi Y strain forms, with the involvement of apoptosis and oxidative stress and enzymatic inhibition.

Involvement of NADPH-oxidase enzyme in the nephroprotective effect of (-)-α-bisabolol on HK2 cells exposed to ischemia – Reoxygenation

Article

Apr 2019
EUR J PHARMACOL

Acute Kidney Injury (AKI) is associated with high morbidity and mortality. Ischemia and reperfusion (I/R) are events that lead to AKI through hypoxia, reactive oxygen species (ROS) production, oxidative stress and apoptosis. We aimed to evaluate the mechanism of nephroprotection mediated by Bisabolol in human tubular kidney cells after injury by I/R in vitro. HK2 cells were exposed to I/R and treated with Bisabolol. Cell viability was accessed by MTT assay. Cells were submitted to flow cytometry to evaluate necrotic/apoptotic cells, reactive oxygen species production and mitochondrial transmembrane depolarization. TBARS and GSH were used as parameters of redox balance. Also, KIM-1 supernatant levels were measured. In order to identify an interaction between bisabolol and NOX4, molecular docking and enzymatic assays were performed. Expression of isoform NOX4 on treated cells was examined by western-blot. Finally, cells were visualized by scanning electron microscopy. Bisabolol improved cell viability and prevented cell death by apoptosis, indicated also by the decreased levels of KIM-1. It was observed a decrease on reactive oxygen species production and mitochondrial depolarization, with antioxidant regulation by increased GSH and decreased lipid peroxidation. It was also demonstrated that bisabolol treatment can inhibit NOX4. Finally, SEM images showed that bisabolol reduced I/R-induced cell damage. Bisabolol treatment protects HK2 cells against oxidative damage occasioned by I/R. This effect is related to inhibition of apoptosis, decrease on KIM-1 release, reactive oxygen species accumulation and mitochondrial dysfunction. Bisabolol inhibited NOX4 activity in the tubular cells, impairing reactive oxygen species synthesis.

Identification of the Bisabolol Synthase in the Endangered Candeia Tree (Eremanthus erythropappus (DC) McLeisch)

Article

Full-text available

Sep 2018

Candeia (Eremanthus erythropappus (DC) McLeisch, Asteraceae) is a Brazilian tree, mainly occurring in the cerrado areas. From ethnobotanical information its essential oil is known to have wound healing and nociceptive properties. These properties are ascribed to result from a sesquiterpene alcohol, (–)-α-bisabolol, which is present at high concentrations in this oil. Bisabolol is highly valued by the cosmetic industry because of its antibacterial, anti-inflammatory, skin-smoothing and wound healing properties. Over the past decades, Candeia timber has been collected at large scale for bisabolol extraction from wild reserves and the species is thereby at risk of extinction. To support the development of breeding and nursing practices that would facilitate sustainable cultivation of Candeia, we identified a terpene synthase gene, EeBOS1, that appears to control biosynthesis (–)-α-bisabolol in the plant. Expression of this gene in E. coli showed that EeBOS1 protein is capable of producing (–)-α-bisabolol from farnesyl pyrophosphate in vitro. Analysis of gene expression in different tissues from Candeia plants in different life stages showed a high correlation of EeBOS1 expression and accumulation of (–)-α-bisabolol. This work is the first step to unravel the pathway toward (–)-α-bisabolol in Candeia, and in the further study of the control of (–)-α-bisabolol production.

Efficient lysis of B-chronic lymphocytic leukemia cells by the plant-derived sesquiterpene alcohol α-bisabolol, a dual proapoptotic and antiautophagic agent

Article

Full-text available

May 2018

The sesquiterpene α-bisabolol (α-BSB) is a cytotoxic agent against acute leukemia and chronic myeloid leukemia cells. Here the profile of α-BSB citotoxicity was evaluated ex vivo in primary mononuclear blood cells isolated from 45 untreated B-chronic lymphocytic leukemia (B-CLL) patients. We studied the effects of α-BSB by flow cytometric and western blotting techniques with the following findings: (1) α-BSB was an effective proapoptotic agent against B-CLL cells (IC50 42 ± 15 μM). It was also active, but to a lesser extent, on normal residual B cells and monocytes (IC50 68 ± 34 and 74 ± 28 μM, respectively; p < 0.01), while T-cells, though not achieving IC50, were nevertheless decreased. (2) Lipid raft content positively correlated with α-BSB cell sensitivity, while neither the phenotype of B-CLL cells nor the disease clinical stage did affect the sensitivity to α-BSB. (3) Flow cytometry analysis evidenced the induction of pores in mitochondrial and lysosomal membrane after 3- to 5-hour exposure of B-CLL cells to α-BSB, leading to apoptosis; in contrast, western blotting analysis showed inhibition of the autophagic flux. Therefore, according to cellular selectivity, α-BSB is a cytotoxic agent preferentially active against leukemic cells, while its lower activity on normal B cells, monocytes and T cells may account for an additive anti-inflammatory effect targeting the leukemia-associated pro-inflammatory microenvironment. Consistent with the observed effects on intracellular processes, α-BSB should be regarded as a dual agent, both activating mitochondrial-based apoptosis and inhibiting autophagy by disrupting lysosomes.

In Vitro Elucidation of Drug Combination Synergy in Treatment of Pancreatic Ductal Adenocarcinoma

Article

Apr 2018
ANTICANCER RES

Background/aim: Advances in therapies targeting proteins and pathways affected by genetic alterations has raised the possibility of personalized cancer treatments. Materials and methods: The efficacy of targeting molecular aberrations was determined in the pancreatic ductal adenocarcinoma (PDAC) cell line, CAPAN2. Two mutations were targeted, KRAS (p.G12V) and ABL1 (p.G1060D), and cells were treated with regorafenib and trametinib, individually and in combination. Results: Exposure to either drug significantly increased cell death compared to the current standard of care, gemcitabine. Treatment with combinations of the drugs led to significant increases in cell death compared to either monotherapy. Strong additive/synergistic interactions were observed across a range of dosages and ratios, reducing dose requirements with potential clinical relevance. Conclusion: The data obtained in this PDAC cell model: i) support the use of matched monotherapies; ii) indicate the effectiveness of matched combination therapies; and iii) provide potential proof-of-concept for precision medicine approach to cancer treatment.

Evidence for the involvement of the GABAergic, but not serotonergic transmission in the anxiolytic-like effect of bisabolol in the mouse elevated plus maze

Article

Full-text available

Oct 2017
N Schmied Arch Pharmacol

Bisabolol (α-(−)-bisabolol) is a sesquiterpene which is a part of the essential oil of a variety of plants, but its common source is German chamomile. Several bioactivities including anti-inflammatory, anti-nociceptive, and anti-tumor effects were attributed to bisabolol. However, the neuropharmacological properties of bisabolol have not yet been reported. The present study evaluated behavioral effects of bisabolol using elevated plus maze (EPM), open field test (OFT), and rotarod test. Moreover, this study also examined whether the 5-HT1A and GABAA–benzodiazepine receptor systems are involved in the anxiolytic-like effects of bisabolol. After acute intraperitoneal treatment with bisabolol at the doses of 0.5, 1, 2, 5, and 10 mg/kg, OFT, EPM, and rotarod were utilized for investigating behavioral effects. Flumazenil, a benzodiazepine receptor antagonist, and WAY-100635, a 5-HT1A receptor antagonist, were used to determine the action mechanism in the EPM. Bisabolol especially at the dose of 1 mg/kg was effective in increasing the total number of entries and time spent in the open arms of EPM while number of rearing and grooming in OFT was decreased in comparison to the control. In the rotarod, permanence time was decreased in the mice treated with the high doses of bisabolol. Pretreatment with flumazenil, but not WAY-100635, was able to reverse the effect of bisabolol 1 mg/kg in the EPM, indicating that the anxiolytic-like activity of bisabolol occurs via the GABAergic but not serotonergic transmission. The present study supports the idea that bisabolol may mediate its anxiolytic-like and sedative mechanisms involving GABAA receptors.

Myrcia splendens (Sw.) DC. (syn. M. fallax (Rich.) DC.) (Myrtaceae) Essential Oil from Amazonian Ecuador: A Chemical Characterization and Bioactivity Profile

Article

Full-text available

Jul 2017
MOLECULES

In this study, we performed the chemical characterization of Myrcia splendens (Sw.) DC. (Myrtaceae) essential oil from Amazonian Ecuador and the assessment of its bioactivity in terms of cytotoxic, antibacterial, and antioxidant activity as starting point for possible applicative uses. M. splendens essential oil, obtained by hydro-distillation, was analyzed by Gas Chromatography-Mass Spectrometry (GC-MS) and Gas Chromatography-Flame Ionization Detector (GC-FID): the major components were found to be trans-nerolidol (67.81%) and α-bisabolol (17.51%). Furthermore, we assessed the cytotoxic activity against MCF-7 (breast), A549 (lung) human tumor cell lines, and HaCaT (human keratinocytes) non-tumor cell line through 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) test: promising results in terms of selectivity and efficacy against the MCF-7 cell line (IC50 of 5.59 ± 0.13 μg/mL at 48 h) were obtained, mainly due to α-bisabolol. Furthermore, antibacterial activity against Gram positive and negative bacteria were performed through High Performance Thin Layer Chromatography (HPTLC) bioautographic assay and microdilution method: trans-nerolidol and β-cedren-9-one were the main molecules responsible for the low antibacterial effects against human pathogens. Nevertheless, interesting values of Minimum Inhibitory Concentration (MIC) were noticeable against phytopathogen strains. Radical scavenging activity performed by HPTLC bioautographic and spectrophotometric 1,1-diphenyl-2-picrylhydrazyl (DPPH) approaches were negligible. In conclusion, the essential oil revealed a good potential for plant defense and anti-cancer applications.

Alpha-bisabolol, not a matter for cancer therapy. Commentary: "Research on the immunosuppressive activity of ingredients contained in sunscreens".

Article

May 2015

Salvatore Chirumbolo

Functional Ingredients Analysis for the Leaves of Premna ligustroides Hemsl. and the Antioxidant Activity Evaluation for its Ethanol Extracts

Article

Nov 2015

Premna ligustroides Hemsl. is a traditional plant food material, but the chemical components, functional ingredients of the leaves and its antioxidant activity of ethanol extracts had never been studied. In this study, the moisture, ash, crude fiber, crude fatty, pectin, and amino acid were 8.95 +/- 0.01, 7.76 +/- 0.06, 7.86 +/- 0.10, 12.93 +/- 0.05, 19.21 +/- 0.02, and 15.26 +/- 0.16 g/100 g dry basis, respectively. Total flavonoids content of leaves was 74.35 +/- 0.49 mg/g. Degree of esterification (DE) of the pectin was 66.67 +/- 1.02%, and the unsaturated fatty acids occupied 64.71% of the total fatty acids, 17 amino acids which contained seven essential amino acids were detected. Fifty eight volatile compounds were separated and identified. The extracted flavonoids had higher reducing power than ascorbic acid at the same concentration, and had significant scavenging abilities on hydroxyl radicals, superoxide anion radical, and DPPH radical. The results indicated that the leaves of P ligustroides Hemsl. as a kind of botanical food has a great value of development and utilization.

Alpha-bisabolol, not a matter for cancer therapy. Commentary: “Research on the immunosuppressive activity of ingredients contained in sunscreens”

Article

May 2015

Salvatore Chirumbolo

EGR-1/Bax Pathway Plays a Role in Vitamin E δ-Tocotrienol-induced Apoptosis in Pancreatic Cancer Cells

Article

Apr 2015

The anticancer activity of δ-tocotrienol, a bioactive vitamin E present in whole grain cereals, annatto beans and palm fruit, is strongly dependent on its effect on the induction of apoptosis. δ-Tocotrienol-induced apoptosis is associated with consistent induction in the expression of the proapoptotic protein Bcl-2-associated X protein (Bax). The molecular mechanism by which δ-tocotrienol regulates Bax expression is unknown. We carried out a DNA microarray study that identified δ-tocotrienol induction of the zinc finger transcription factor EGR-1 in pancreatic cancer cells. Here, we provide evidence linking δ-tocotrienol-induced apoptosis in pancreatic cancer cells to EGR-1 regulation of Bax expression. Forced expression of EGR-1 induces Bax expression and apoptosis in pancreatic cancer cells. In contrast, knockdown of δ-tocotrienol-induced EGR-1 by small interfering RNA attenuated δ-tocotrienol-induced Bax expression and reduced δ-tocotrienol-induced apoptosis. Further analyses showed that de novo protein synthesis was not required for δ-tocotrienol-induced EGR-1 expression, suggesting a direct effect of δ-tocotrienol on EGR-1 expression. Furthermore, a chromatin immunoprecipitation assay demonstrated that EGR-1 binds to the Bax gene promoter. Finally, δ-tocotrienol treatment induced Bax expression and activated EGR-1 in the pancreatic neoplastic cells of the PDX-Cre Kras genetically engineered model of pancreatic cancer. Our study provides the first evidence for EGR-1 as a direct target of vitamin E δ-tocotrienol, suggesting that EGR-1 may act as a proapoptotic factor in pancreatic cancer cells via induction of Bax. Copyright © 2015. Published by Elsevier Inc.

Differential modulation of nicotine-induced gemcitabine resistance by GABA receptor agonists in pancreatic cancer cell xenografts and in vitro

Article

Full-text available

Sep 2014
BMC CANCER

Background Pancreatic cancer is frequently resistant to cancer therapeutics. Smoking and alcoholism are risk factors and pancreatic cancer patients often undergo nicotine replacement therapy (NRT) and treatment for alcohol dependence. Based on our report that low dose nicotine within the range of NRT causes gemcitabine resistance in pancreatic cancer, our current study has tested the hypothesis that GABA or the selective GABA-B-R agonist baclofen used to treat alcohol dependence reverse nicotine-induced gemcitabine resistance in pancreatic cancer. Methods Using mouse xenografts from the gemcitabine--sensitive pancreatic cancer cell line BXPC-3, we tested the effects of GABA and baclofen on nicotine-induced gemcitabine resistance. The levels of cAMP, p-SRC, p-ERK, p-AKT, p-CREB and cleaved caspase-3 in xenograft tissues were determined by ELISA assays. Expression of the two GABA-B receptors, metalloproteinase-2 and 9 and EGR-1 in xenograft tissues was monitored by Western blotting. Mechanistic studies were conducted in vitro, using cell lines BXPC-3 and PANC-1 and included analyses of cAMP production by ELISA assay and Western blots to determine protein expression of GABA-B receptors, metalloproteinase-2 and 9 and EGR-1. Results Our data show that GABA was as effective as gemcitabine and significantly reversed gemcitabine resistance induced by low dose nicotine in xenografts whereas baclofen did not. These effects of GABA were accompanied by decreases in cAMP, p-CREB, p-AKT, p-Src, p-ERK metalloproteinases-9 and -2 and EGR-1 and increases in cleaved caspase-3 in xenografts whereas baclofen had the opposite effects. In vitro exposure of cells to single doses or seven days of nicotine induced the protein expression of MMP-2, MMP-9 and EGR-1 and these responses were blocked by GABA. Baclofen downregulated the protein expression of GABA-B-Rs in xenograft tissues and in cells exposed to baclofen for seven days in vitro. This response was accompanied by inversed baclofen effects from inhibition of cAMP formation after single dose exposures to stimulation of cAMP formation in cells pretreated for seven days. Conclusions These findings suggest GABA as a promising single agent for the therapy of pancreatic cancer and to overcome nicotine-induced gemcitabine resistance whereas treatment with baclofen may increase gemcitabine resistance.

Terpenes

Chapter

Feb 2023

Terpenes are the largest and most diverse group of naturally occurring compounds found in plants. They can be classified according to the number of isoprene units, the most common being monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), and triterpenes (C30). Besides being the principal constituents of essential oils and playing fundamental roles in plants, many terpenes are extensively used in pharmaceutical and industrial applications ranging from flavours to fragrances and medicines. Several studies have already demonstrated the diversity of terpenes’ biological properties, including cancer chemopreventive effects, antimicrobial, antiviral, analgesic, anti-inflammatory, antifungal, antiparasitic, and other activities. This chapter compiles the various terpenes isolated from plants, their sources, biological activities and beneficial health effects, mechanism of action, extraction and applications, and the future perspective for using the terpenes as lead molecules in several areas of the industry.

Biological Activities of the Fruit Essential Oil, Fruit, and Root Extracts of Ferula drudeana Korovin, the Putative Anatolian Ecotype of the Silphion Plant

Article

Full-text available

Feb 2023

Preliminary phytochemical investigations were performed on the fruit essential oil and antioxidant-rich methanolic extracts of the fruits and roots of Ferula drudeana, the putative Anatolian ecotype of the Silphion plant, to corroborate its medicinal plant potential and identify its unique characteristics amongst other Ferula species. The essential oil from the fruits of the endemic species Ferula drudeana collected from Aksaray was analyzed by GC and GC/MS. The main components of the oil were determined as shyobunone (44.2%) and 6-epishyobunone (12.6%). The essential oil of the fruits and various solvent extracts of the fruits and roots of F. drudeana were evaluated for their antibacterial and anticandidal activity using microbroth dilution methods. The essential oil of the fruits, methanol, and methylene chloride extracts of the fruits and roots showed weak to moderate inhibitory activity against all tested microorganisms with MIC values of 78–2000 μg/mL. However, the petroleum ether extract of the roots showed remarkable inhibitory activity against Candida krusei and Candida utilis with MIC values of 19.5 and 9.75 μg/mL, respectively. Furthermore, all the samples were tested for their antioxidant activities using DPPH• TLC spot testing, online HPLC–ABTS screening, and DPPH/ABTS radical scavenging activity assessment assays. Methanolic extracts of the fruits and roots showed strong antioxidant activity in both systems.

Role of Terpenoids as Anticancer Compounds: An Insight into Prevention and Treatment

Chapter

Jul 2022

This book provides an update on heterocyclic compounds that serve as key components of anti-cancer agents administered in pre-clinical settings. Many of the compounds highlighted in the book are being actively investigated for the bioactive properties against a range of cancer cell lines. There is potential for heterocyclic compounds to design agents that can target specific molecules to treat different types of cancers. Chapters are contributed by experts in pharmaceutical chemistry and are written to give a general overview of the topic to readers involved in all levels of research and decision-making in pharmaceutical chemistry and anti-cancer drug design. Part 1 of the book set covers these topics: - Heterocyclic anticancer compounds derived from natural sources with their mechanism of action - The role of terpenoids as anticancer compounds: an insight into prevention and treatment - Recent advances in synthesis and anticancer activity of benzothiazole hybrids as anticancer agents - Structure-activity relationship studies of novel hybrid quinoline and quinolone derivatives as anticancer agents - Tetrazoles: structure and activity relationship as anticancer agents - Progress in nitrogen and oxygen-based heterocyclic compounds for their anticancer activity: an update (2017-2020)

Pharmacological and biological effects of alpha-bisabolol: An updated review of the molecular mechanisms

Article

Jun 2022

Alpha-bisabolol (α-bisabolol), an unsaturated monocyclic sesquiterpene alcohol, is known as one of the "most-used herbal constituents" in the world. Various therapeutic and biological properties of α-bisabolol in preventing oxidative stress, inflammatory disorders, infections, neurodegenerative diseases, cancers, and metabolic disorders have been reported. In this review, we evaluated new findings regarding the molecular mechanisms of α-bisabolol published from 2010 until 2021 in PubMed, Science Direct, and Scopus. The antioxidant mechanism of α-bisabolol is mainly associated with the reduction of ROS/RNS, MDA, and GSH depletion, MPO activity, and augmentation of SOD and CAT. Additionally, upregulating the expression of bcl-2 and suppression of bax, P53, APAF-1, caspase-3, and caspase-9 activity indicates the anti-apoptotic effects of α- bisabolol. It possesses anti-inflammatory effects via reduction of TNF-α, IL-1β, IL-6, iNOS, and COX-2 and suppresses the activation of ERK1/2, JNK, NF-κB, and p38. The antimicrobial effect is mediated by inhibiting the viability of infected cells and improves cognitive function via downregulation of bax, cleaved caspases-3 and 9 levels, β-secretase, cholinesterase activities, and upregulation of bcl-2 levels. Finally, due to multiple biological activities, α-bisabolol is worthy to be subjected to clinical trials to achieve new insights into its beneficial effects on human health.

Triclosan and ⍺-bisabolol–loaded nanocapsule functionalized with ascorbic acid as a dry powder formulation against A549 lung cancer cells

Article

Jun 2022
J DRUG DELIV SCI TEC

Lung cancer is between the primary causes of cancer death showing a high mortality rate. Traditional therapies lead to serious side-effects pushing the development of new and more specific treatments. This study proposes an innovative inhalable powder intended for lung cancer on-site action, by developing new nanocapsules functionalized powder formulation carrying triclosan, dispersed in α-bisabolol and functionalized with ascorbic acid. Nanocapsules were obtained by interfacial deposition of the preformed polymer method. Functionalization was performed via a three-step interfacial reaction process forming a chitosan-iron-ligand complex. After spray-drying, powders were obtained using two strategies. All formulations were characterized and had their antiproliferative activities tested, along with their irritability potential. Functionalized nanocapsules were subsequently spray-dried to produce dispersible powders. Using combined data from infrared spectroscopy was observed an interaction between the components after each step of the surface functionalization. The same components interactions were verified before and after obtaining the powder, which were adequate for lung administration, suffering deposition mainly in the respirable fraction within 15 min. The powder showed an effective concentration against lung cancer cells (A549), with nontoxic effects in irritability assay. By the results, the formulation can be administered at safe triclosan concentrations. Thus, the proposed formulations are appropriate and promising candidates for further research in lung cancer treatment.

Applications of heteropoly acids in industry

Chapter

Jan 2022

Due to the importance of heteropoly acids as solid acids in organic chemistry and industrial, this chapter highlights the applications of heteropoly acids in the chemical industry (e.g., desulfurization), pharmaceutical, the food industry, biomass, and removal of pollutants. In recent decades, desulfurization of gasoline has received increasing attention, chiefly for environmental reasons. One feasible approach to resolve this is hydrodesulfurization (HDS), while hydrogenation is an energy-consuming process decreasing the octane number and the quality of gasoline. Dietary phytosterols including phytostanols are believed to effectively lower the absorption of cholesterol. A number of ways have been suggested to increase the solubility or bioavailability of phytosterols. Phytosteryl esters are much more soluble than the free phytosterols in the oil phase. Therefore, using phytosteryl esters in oil has been proposed in order to lower cholesterol absorption. Biomass resources are regarded as a good choice for raw material supply in the production of high-value products due to their low cost, accessibility, sufficiency, and renewability. Many industries are focusing on the production of chemicals and other products from biomass such as lactic acid, levulinic acid, formic acid, biodiesel, and cellulose derivatives. The deposition of solid waste generated by various industries that pollutes water, air, and soil is one of the main environmental issues. Green chemistry dictates that the elimination or reduction of hazardous waste and substances must be considered in every chemical/industrial process. Great developments have been achieved regarding the application of heteropoly acids in this area, and a few examples are addressed in this chapter.

In vitro and in vivo investigation of polypharmacology of propolis extract as anticancer, antibacterial, anti-inflammatory, and chemical properties

Article

Full-text available

Aug 2021

Numerous compounds derived from natural sources such as microbes, plants, and insects have proven to be safe, efficacious, and cost-effective therapeutics for human diseases. This study examined the bioactivities of propolis, a structural sealant and antibacterial/antifungal agent produced by honey bees. Chinese propolis was extracted in methanol or hexane. Propolis significantly reduced the numbers of viable cancer cells when applied as a methanol extract (IC 50 values in μg/mL for the indicated cell line: MDA-MB-231, 74.12; LoVo, 74.12; HepG2, 77.74; MCF7, 95.10; A549, 114.84) or a hexane extract (MDA-MB-231, 52.11; LoVo, 45.9; HepG2, 52.11; MCF7, 78.01; A549, 67.90). Hexane extract also induced apoptosis of HepG2 cells according to activated caspase-3/7 expression assays (17.6 ± 2.9% at 150 μg/mL and 89.2 ± 1.9% at 300 μg/mL vs 3.4 ± 0.4% in vehicle control), suppressed the growth of Candida albicans and multiple multidrug-resistant and nonresistant Gram-positive bacteria, and inhibited croton oil-induced skin inflammation when applied as topical treatment. GC-MS identified hexadecanoic acid methyl ester as a major constituent (33.6%). Propolis hexane extract has potential anticancer, antimicrobial, and anti-inflammatory activities.

α-Bisabolol protects against β-adrenergic agonist-induced myocardial infarction in rats by attenuating inflammation, lysosomal dysfunction, NLRP3 inflammasome activation and modulating autophagic flux

Article

Nov 2019

Emerging evidence demonstrate that NLRP3 inflammasome activation, lysosomal dysfunction, and impaired autophagic flux plays crucial role in the pathophysiology of myocardial infarction (MI). Therapeutic strategies targeting NLRP3 activation, lysosomal enzymes...

Chemical Composition of Essential Oils of Four Tanacetum Species from the Alpine Regions in Iran

Article

Oct 2019
J ESSENT OIL BEAR PL

Abdollah Ghasemi Pirbalouti

Essential oils from the inflorescences of Tanacetum kotschyi and T. persicum, aerial parts of T. chiliophyllum and T. polycephalum collected from the alpine area of Zagros Mountains (2700-3000 m) in Southwest Iran were analyzed by GC-FID and GC/MS. Essential oil yields of four Tanacetum species ranged from 0.25 to 0.55 ml/100 g dry material. Results of the analysis indicated chemical differences among the four Tanacetum species. The main constituents of the essential oils were linalool, camphor, trans-chrysanthenyl acetate, carvacrol, cis-chrysanthenol, and thymol for T. chiliophyllum; α-bisabolol, camphor, carvacrol, and 1,8-cineole for T. kotschyi; borneol, and bornyl acetate for T. persicum; 1,8-cineole, borneol, bornyl acetate, and camphor for T. polycephalum. The essential oils of the four studied Tanacetum species sourced in the alpine region of southwestern Iran were rich in oxygenated monoterpenes, which are widely used in food and drug industries.

α-bisabolol enhances radiotherapy-induced apoptosis in endometrial cancer cells by reducing the effect of XIAP on inhibiting caspase-3

Article

Full-text available

May 2019

Endometrial cancer (EC) is one of the most common cancers in females. Although the diagnosis and treatment in early stages can greatly improve the survival rate of patients, the advanced EC still is lethal. Radiotherapy is widely used against EC, and it is a great challenge to find an effective way to overcome the resistance of EC during radiotherapy. α-bisabolol is a promising drug, which has already exhibited its anti-tumor effect in some malignancies. Here we reported that α-bisabolol could inhibit the proliferation of EC cells. It is also shown that their abilities of migration and invasion were effectively reduced by α-bisabolol. Furthermore, our results also demonstrated that α-bisabolol could improve sensitivity of EC cells in radiotherapy and further inhibited the growth of EC cells. By Western blot, we found the expression of matrix metalloproteinases-9 (MMP-9) and cyclin E were significantly decreased, which indicated that EC cells can be further suppressed by using α-bisabolol and radiotherapy. It is also demonstrated in our study that the rate of apoptotic cells is markedly increased in EC by using these two treatments. The significant decrease in X-linked inhibitor of apoptosis protein (XIAP) and increase in caspase-3 detected in our study suggested that the enhancement of apoptosis is mediated by XIAP/caspase-3 pathway, which was further confirmed by examining the downstream effectors of caspase-3, COX-2, PARP and cleaved PARP. In the present study, we demonstrated that α-bisabolol could enhance the sensitivity of EC cells to radiotherapy, which provide a novel alternative for overcoming radioresistance of EC cells and achieving a better outcome in radiotherapy.

Protective effects of α‐bisabolol on altered hemodynamics, lipid peroxidation, and nonenzymatic antioxidants in isoproterenol‐induced myocardial infarction: In vivo and in vitro evidences

Article

Aug 2018

The effect of α‐bisabolol on hemodyanimcs, lipid peroxidation, and nonenzymatic antioxidants was evaluated in isoproterenol‐induced myocardial infarction in rats. They were pre‐ and cotreated with α‐bisabolol (25 mg/kg body weight) daily for 10 days along with the subcutaneous injection of isoproterenol (85 mg/kg body weight) at an interval of 24 hours for 2 days (9th and 10th days). Increased activities of serum creatine kinase and creatine kinase‐MB along with altered levels/concentrations of lipid peroxidation products and nonenzymatic status were observed in the plasma and heart tissues of rats. Treatment with α‐bisabolol showed protective effects by reversing the altered biochemical parameters and hemodynamics studied. The in vitro reducing power of α‐bisabolol confirmed its potent antioxidant action. These biochemical benefits were translated into functional recovery by the maintenance of the hemodynamics in rats. The findings showed that α‐bisabolol has the potential to protect against isoproterenol‐induced myocardial infarction due to its potent antilipid peroxidation and antioxidant properties.

Structural and Chemical Biology of Terpenoid Cyclases

Article

Aug 2017

David W. Christianson

The year 2017 marks the twentieth anniversary of terpenoid cyclase structural biology: a trio of terpenoid cyclase structures reported together in 1997 were the first to set the foundation for understanding the enzymes largely responsible for the exquisite chemodiversity of more than 80000 terpenoid natural products. Terpenoid cyclases catalyze the most complex chemical reactions in biology, in that more than half of the substrate carbon atoms undergo changes in bonding and hybridization during a single enzyme-catalyzed cyclization reaction. The past two decades have witnessed structural, functional, and computational studies illuminating the modes of substrate activation that initiate the cyclization cascade, the management and manipulation of high-energy carbocation intermediates that propagate the cyclization cascade, and the chemical strategies that terminate the cyclization cascade. The role of the terpenoid cyclase as a template for catalysis is paramount to its function, and protein engineering can be used to reprogram the cyclization cascade to generate alternative and commercially important products. Here, I review key advances in terpenoid cyclase structural and chemical biology, focusing mainly on terpenoid cyclases and related prenyltransferases for which X-ray crystal structures have informed and advanced our understanding of enzyme structure and function.

Chemical Composition of the Essential Oils from the Leaves and Flowers of Two Achillea species from Iran

Article

Jan 2017
J ESSENT OIL BEAR PL

Abdollah Ghasemi Pirbalouti

The aerial parts of wild Achillea wilhelmsii C. Koch and A. kellalensis Boiss. & Hausskn. (Asteraceae family) were collected from Southwestern Iran provinces. The essential oils obtained by steam distillation from fine powder of the leaves and flowers of the two Achillea species have been analyzed by GC and GC-MS. The oil yield varied of 0.23 to 0.68% dry matter. The variations in chemical compositions from the flowers and leaves are important between plant populations. A total of 46 constituents were identified. The major constituents of the essential oils of A. wilhelmsii collected from the Ben and Natanz regions were lavandulyl acetate (t 26.2%), chrysanthenone (t 18.3%), 1,8-cineole (5.5 17.2%), linalool (0.8 16.1%), camphor (0.5 16.6%), borneol (t 6.5%), α-pinene (2.7 6.5%) and lavandulol (t 6.0%), while the essential oils of A. kellalensis from the Kallar region were chamazulene (49.0 52.6%), α-bisabolol (20.5 -25.1%), β-myrcene (2.8 3.7%), and αpinene (1.6 4.5%). Although, the essential oils from the flowers and leaves of A. kellalensis were characterized by high level of oxygenated sesquiterpenes, those of A. wilhelmsii were characterized by high level of oxygenated monoterpenes.

Sesquiterpenes from Essential Oils with Promising Antitumor Properties

Chapter

Sep 2015

Cancer remains the leading cause of human mortality worldwide. Despite some decline in the mortality rates from the past two decades, cancer claims millions of deaths each year. Chemotherapy using natural products had proved its potential against cancer in recent times. Currently more than 60 % of Food and Drug Administration (FDA)-approved drugs against different diseases are from either natural products or their synthetic derivatives. Sesquiterpenes are natural products which can be found in essential oils. These compounds have been found to have antitumor activities both in vitro and in vivo. A growing body of evidence suggests that these compounds could induce apoptosis, a non-pathological form of cell death, in different tumors. Many of these sesquiterpenes have also been shown to inhibit tumor progression by inhibiting the process of angiogenesis. Sesquiterpenes from essential oils have been shown to target various critical tumor-driving signaling pathways. Moreover, the most striking feature of sesquiterpenes is that some of these molecules can synergize the effect of current chemotherapeutic agents. Keeping in view the therapeutic potential of the sesquiterpenes from essential oils, more comprehensive per-clinical studies need to be performed in this direction.

Les matricaires, des « camomilles » d’intérêt pour la phyto-aromathérapie

Article

Jun 2016

F. Petitet

Among the “Chamomille”, Matricaria species constitute an homogeneous botanical group of interest for phytotherapists. More particularly the german chamomille, Matricaria recutita, is largely described in the scientific literature for its sedative, digestive effect and use in dermoinflammatory diseases.

Biological Activities of Essential Oils: An Update

Chapter

Nov 2015

Heteropoly acid catalyzed cyclization of nerolidol and farnesol: Synthesis of α-bisabolol

Article

Jun 2015
APPL CATAL A-GEN

Heteropoly acid H3PW12O40 is an active and environmentally friendly homogeneous catalyst for the synthesis of α-bisabolol, a high-priced and highly demanded ingredient for the fragrance, cosmetic and pharmaceutical industries, starting from more abundant biomass-based sesquiterpenic alcohols. The solvent nature remarkably affects the reaction pathways and product selectivity. In acetone solutions, α-bisabolol can be obtained in 55–60% GC yields from nerolidol and 60–70% GC yields from farnesol at complete substrate conversions, which are probably the best results ever reported for these reactions. α-Bisabolol synthesized by this method contains no farnesol, which is a potentially allergenic compound and should be avoided in the commercially used α-bisabolol. This advantage is especially important because the distillative separation of α−bisabolol and farnesol is a troublesome task. The catalyst shows high turnover numbers and operates under mild nearly ambient conditions.

Natural Products

Chapter

May 2013

Reports on the biological properties of mono- and sesquiterpenes (MTs and SQTs) have been on the increase. Although MTs and SQTs are already in wide use as flavoring and antimicrobial agents in cosmetics, perfumes, household and cleansing products, and food additives, many of their pharmacological properties are yet to be discovered. Studies report on their anticancer, antiinflammatory, antinociceptive, antidiabetic, and antimicrobial activities and effects on the central nervous system that make them potential targets for development of new therapeutics and for usage for medical purposes. This chapter provides an overview of the biological activities and aromatherapeutic uses of chemical classes of MTs and SQTs, compiling the scientific achievements mainly from 2010, 2011, and the first part of 2012. Because hundreds of MTs and SQTs and their derivates exist, only some prominent representatives of MT- and SQT-hydrocarbons, -alcohols, -oxides and -carbonyls are discussed.

Potential New Pharmacological Agents Derived From Medicinal Plants for the Treatment of Pancreatic Cancer

Article

Jan 2015

In the present article, we reviewed plants and phytochemical compounds demonstrating beneficial effects in pancreatic cancer to find new sources of pharmaceutical agents. For this purpose, Scopus, PubMed, Web of Science, and Google scholar were searched for plants or herbal components with beneficial effects in the treatment of pancreatic cancer. Data were collected up to January 2013. The search terms were "plant," "herb," "herbal therapy," or "phytotherapy" and "pancreatic cancer" or "pancreas." All of the human in vivo and in vitro studies were included. According to studies, among diverse plants and phytochemicals, 12 compounds including apigenin, genistein, quercetin, resveratrol, epigallocatechin gallate, benzyl isothiocyanate, sulforaphane, curcumin, thymoquinone, dihydroartemisinin, cucurbitacin B, and perillyl alcohol have beneficial action against pancreatic cancer cells through 4 or more mechanisms. Applying their plausible synergistic effects can be an imperative approach for finding new efficient pharmacological agents in the treatment of pancreatic cancer.

Apoptotic pathways in pancreatic ductal adenocarcinoma

Article

Full-text available

Jul 2008
MOL CANCER

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer related death. Despite the advances in understanding of the molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. Overall, the 5-year survival rate is less than 5% demonstrating the insufficiency of current therapies. Most cytotoxic therapies induce apoptosis and PDAC cells have evolved a plethora of molecular mechanisms to assure survival. We will present anti-apoptotic strategies working at the level of the death receptors, the mitochondria or involving the caspase inhibitors of the IAP family. Furthermore, the survival function of the phosphotidylinositol-3' kinase (PI3K)/AKT- and NF-kappaB-pathways are illustrated. A detailed molecular knowledge of the anti-apoptotic mechanisms of PDAC cells will help to improve therapies for this dismal disease and therapeutic strategies targeting the programmed cell death machinery are in early preclinical and clinical development.

Content and composition of the essential oil of Chamomilla recutita (L.) Rauschert from some European countries

Article

Full-text available

Jan 2010

Variations in the essential oil composition of Chamomilla recutita (L.) Rauschert from different European countries were determined. A total of 39 components were identified, representing over 92% of the total oil yield. The principal biologically active compounds in chamomile oils were bisabolol oxide A (3.1-56.0%), alpha-bisabolol (0.1-44.2%), bisabolol oxide B (3.9-27.2%), cis-enyne-bicycloether (8.8-26.1%), bisabolon oxide A (0.5-24.8%), chamazulene (0.7-15.3%), spathulenol (1.7-4.8%) and (E)-beta-farnesene (2.3-6.6%). In 8 chamomile samples from 13, bisabolol oxide A (27.5-56.0%) was predominant (among them in three Estonian samples). alpha-Bisabolol (23.9-44.2%) was predominant in the samples from Moldova, Russia and the Czech Republic. The sample from Armenia was rich in bisabolol oxide B (27.2%) and chamazulene (15.3%). The oils were obtained in yields of 0.7-6.7 mL kg(-1) and the minimum limit of 4 mL kg(-1) stated by the European Pharmacopoeia was exceeded only in 13 samples from 13 analysed drugs.

PTEN regulation by Akt-EGR1-ARF-PTEN axis

Article

Full-text available

Jan 2009
EMBO J

The PTEN tumour suppressor gene is induced by the early growth response 1 (EGR1) transcription factor, which also transactivates p53, p73, and p300/CBP as well as other proapoptotic and anti-cancer genes. Here, we describe a novel Akt-EGR1-alternate reading frame (ARF)-PTEN axis, in which PTEN activation in vivo requires p14ARF-mediated sumoylation of EGR1. This modification is dependent on the phosphorylation of EGR1 at S350 and T309 by Akt, which promotes interaction of EGR1 with ARF at K272 in its repressor domain by the ARF/Ubc9/SUMO system. EGR1 sumoylation is decreased by ARF reduction, and no EGR1 sumoylation is detected in ARF(-/-) mice, which also exhibit reduced amounts of PTEN. Our model predicts that perturbation of any of the clinically important tumour suppressors, PTEN, EGR1, and ARF, will cause some degree of dysfunction of the others. These results also explain the known negative feedback regulation by PTEN on its own synthesis through PI3 kinase inhibition.

PI3K pathway alterations in cancer: Variations on a theme

Article

Full-text available

Oct 2008

The high frequency of phosphoinositide 3-kinase (PI3K) pathway alterations in cancer has led to a surge in the development of PI3K inhibitors. Many of these targeted therapies are currently in clinical trials and show great promise for the treatment of PI3K-addicted tumors. These recent developments call for a re-evaluation of the oncogenic mechanisms behind PI3K pathway alterations. This pathway is unique in that every major node is frequently mutated or amplified in a wide variety of solid tumors. Receptor tyrosine kinases upstream of PI3K, the p110 alpha catalytic subunit of PI3K, the downstream kinase, AKT, and the negative regulator, PTEN, are all frequently altered in cancer. In this review, we will examine the oncogenic properties of these genetic alterations to understand whether they are redundant or distinct and propose treatment strategies tailored for these genetic lesions.

Kaufmann, SH, Desnoyers, S, Ottaviano, Y, Davidson, NE & Poirier, GG. Specific cleavage of poly-(ADP-ribose)-polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res 53: 3976-3985

Article

Full-text available

Oct 1993

Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, the proteolytic cleavage of poly(ADP-ribose) polymerase (pADPRp) during the course of chemotherapy-induced apoptosis was examined. Treatment of HL-60 human leukemia cells with the topoisomerase II-directed anticancer agent etoposide resulted in morphological changes characteristic of apoptosis. Endonucleolytic degradation of DNA to generate nucleosomal fragments occurred simultaneously. Western blotting with epitope-specific monoclonal and polyclonal antibodies revealed that these characteristic apoptotic changes were accompanied by early, quantitative cleavage of the M(r) 116,000 pADPRp polypeptide to an M(r) approximately 25,000 fragment containing the amino-terminal DNA-binding domain of pADPRp and an M(r) approximately 85,000 fragment containing the automodification and catalytic domains. Activity blotting revealed that the M(r) approximately 85,000 fragment retained basal pADPRp activity but was not activated by exogenous nicked DNA. Similar cleavage of pADPRp was observed after exposure of HL-60 cells to a variety of chemotherapeutic agents including cis-diaminedichloroplatinum(II), colcemid, 1-beta-D-arabinofuranosylcytosine, and methotrexate; to gamma-irradiation; or to the protein synthesis inhibitors puromycin or cycloheximide. Similar changes were observed in MDA-MB-468 human breast cancer cells treated with trifluorothymidine or 5-fluoro-2'-deoxyuridine and in gamma-irradiated or glucocorticoid-treated rat thymocytes undergoing apoptosis. Treatment with several compounds (tosyl-L-lysine chloromethyl ketone, tosyl-L-phenylalanine chloromethyl ketone, N-ethylmaleimide, iodoacetamide) prevented both the proteolytic cleavage of pADPRp and the internucleosomal fragmentation of DNA. The results suggest that proteolytic cleavage of pADPRp, in addition to being an early marker of chemotherapy-induced apoptosis, might reflect more widespread proteolysis that is a critical biochemical event early during the process of physiological cell death.

The Phosphatidylinositol 3 Kinase AKT Pathway in human cancer

Article

Full-text available

Aug 2002
NAT REV CANCER

One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K). This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression. Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.

Soldani, C. & Scovassi, A. I. Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis 7, 321-328

Article

Full-text available

Sep 2002

Poly(ADP-ribosylation) is a post-translational modification of proteins playing a crucial role in many processes, including DNA repair and cell death. The best known poly(ADP-ribosylating) enzyme, PARP-1, is a DNA nick sensor and uses betaNAD(+) to form polymers of ADP-ribose which are further bound to nuclear protein acceptors. To strictly regulate poly(ADP-ribose) turnover, its degradation is assured by the enzyme poly(ADP-ribose) glycohydrolase (PARG). During apoptosis, PARP-1 plays two opposite roles: its stimulation leads to poly(ADP-ribose) synthesis, whereas caspases cause PARP-1 cleavage and inactivation. PARP-1 proteolysis produces an 89 kDa C-terminal fragment, with a reduced catalytic activity, and a 24 kDa N-terminal peptide, which retains the DNA binding domains. The fate and the possible role of these fragments during apoptosis will be discussed.

Sensitization of Staphylococcus aureus and Escherichia coli to Antibiotics by the Sesquiterpenoids Nerolidol, Farnesol, Bisabolol, and Apritone

Article

Full-text available

Nov 2003

The sesquiterpenoids nerolidol, farnesol, bisabolol, and apritone were investigated for their abilities to enhance bacterial permeability and susceptibility to exogenous antimicrobial compounds. Initially, it was observed by flow cytometry that these sesquiterpenoids promoted the intracellular accumulation of the membrane-impermeant nucleic acid stain ethidium bromide by live cells of Lactobacillus fermentum, suggesting that enhanced permeability resulted from disruption of the cytoplasmic membrane. The ability of these sesquiterpenoids to increase bacterial susceptibility to a number of clinically important antibiotics was then investigated. In disk diffusion assays, treatment with low concentrations (0.5 to 2 mM) of nerolidol, bisabolol, or apritone enhanced the susceptibility of Staphylococcus aureus to ciprofloxacin, clindamycin, erythromycin, gentamicin, tetracycline, and vancomycin. Nerolidol and farnesol also sensitized Escherichia coli to polymyxin B. Our results indicate the practical utility of sensitizing bacteria to antimicrobials with sesquiterpenoids that have traditionally been used as flavorants and aroma compounds in the food and perfume industries.

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGF beta 1, PTEN, p53, and fibronectin

Article

Full-text available

Mar 2006
CANCER GENE THER

Recent studies are reviewed indicating that the transcription factor early growth response-1 (Egr1) is a direct regulator of multiple tumor suppressors including TGFbeta1, PTEN, p53, and fibronectin. The downstream pathways of these factors display multiple nodes of interaction with each other, suggesting the existence of a functional network of suppressor factors that serve to maintain normal growth regulation and resist the emergence of transformed variants. Paradoxically, Egr1 is oncogenic in prostate cancer. In the majority of these cancers, PTEN or p53 is inactive. It is suggested that these defects in the suppressor network allow for the unopposed induction of TGFbeta1 and fibronectin, which favor transformation and survival of prostate tumor epithelial cells, and explain the role of Egr1 in prostate cancer. Egr1 is a novel and logical target for intervention by gene therapy methods, and targeting methods are discussed.

Nek2 as an Effective Target for Inhibition of Tumorigenic Growth and Peritoneal Dissemination of Cholangiocarcinoma

Article

Full-text available

Nov 2007

We investigated the role of Nek2, a member of the serine/threonine kinase family, Nek, in the tumorigenic growth of cholangiocarcinoma cells. Expression of Nek2 is elevated in cholangiocarcinoma in a tumor-specific manner as compared with that of normal fibroblast cells. Expression of exogenous Nek2 did not perturb the growth of cholangiocarcinoma cells, whereas suppression of the Nek2 expression with siRNA resulted in the inhibition of cell proliferation and induced cell death. In xenograft-nude mouse model, s.c. injection of Nek2 siRNA around the tumor nodules resulted in reduction of tumor size as compared with those of control siRNA injection. In peritoneal dissemination model, Nek2 siRNA-treated mice showed statistically longer survival periods in comparison with those of the control siRNA-treated mice. Taken together, our data indicate a pivotal role of Nek2 in tumorigenic growth of cholangiocarcinoma.

Phosphoinositide 3-kinase signalling pathways

Article

Apr 2001

Doreen A Cantrell

Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3′-OH position of the inositol ring of inositol phospholipids, producing three lipid products: PtdIns(3)P, PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3). These lipids bind to the pleckstrin homology (PH) domains of proteins and control the activity and subcellular localisation of a diverse array of signal transduction molecules. Three major classes of signalling molecule are regulated by binding of D-3 phosphoinositides to PH domains: guanine-nucleotide-exchange proteins for Ρ family GTPases, the TEC family tyrosine kinases such as BTK and ITK in B and T lymphocytes, respectively, and the AGC superfamily of serine/threonine protein kinases. These molecules are activated by a variety of extracellular stimuli and have been implicated in a wide range of cellular processes, including cell cycle progression, cell growth, cell motility, cell adhesion and cell survival.

Targeting the PI3K-Akt pathway in human cancer: Rationale and promise

Article

Jan 2006
CELL

Chemoradiotherapy for locally advanced pancreatic cancer

Article

Jan 2006

Y. Ito

Chemoradiotherapy is regarded as a standard treatment for locally advanced pancreatic cancer since it was recognized that radiotherapy with concurrent 5-fluorouracil prolonged survival when compared to radiotherapy or chemotherapy alone. Various novel agents such as gemcitabine and radiation schedules have been examined in clinical trials to improve the duration of survival in the past two decades. This article reviews the results of clinical trials and describes the current status and the issues regarding radiation technique. dose fractionation. and combination of new novel agent and radiotherapy in the treatment of locally advanced pancreatic cancer.

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

Article

Antitumor Efficacy of Paclitaxel against Human Lung Cancer Xenografts

Article

Dec 1997
CANCER SCI

We examined paclitaxel for anti-tumor activity against human lung cancer xenografts in nude mice and compared its efficacy with that of cisplatin, currently a key drug for lung cancer chemotherapy. Five non-small cell lung cancers (A549, NCI-H23, NCI-H226, NCI-H460 and NCI-H522) and 2 small cell lung cancers (DMS114 and DMS273) were chosen for this study, since these cell lines have been well characterized as regards in vitro and in vivo drug sensitivity. These cells were exposed to graded concentrations of paclitaxel (0.1 to 1000 nM) for 48 h. The 50% growth-inhibitory concentrations (GI50) for the cell lines ranged from 4 to 24 nM, which are much lower than the achievable peak plasma concentration of paclitaxel. In the in vivo study, 4 cell lines (A549, NCI-H23, NCI-H460, DMS-273) were grown as subcutaneous tumor xenografts in nude mice. Paclitaxel was given intravenously as consecutive daily injections for 5 days at the doses of 24 and 12 mg/kg/day. Against every xenograft, paclitaxel produced a statistically significant tumor growth inhibition compared to the saline control. Paclitaxel at 24 mg/kg/day was more effective than cisplatin at 3 mg/kg/day with the same dosing schedule as above, although the toxicity of paclitaxel was similar to or rather lower than that of cisplatin, in terms of body weight loss. In addition, paclitaxel showed potent activity against 2 other lung cancer xenografts (NCI-H226 and DMS114). Therefore, paclitaxel showed more effective, wider-spectrum anti-tumor activity than cisplatin in this panel of 6 lung cancer xenografts. These findings support the potential utility of paclitaxel in the treatment of human lung cancer

South African Salvia species: A review of biological activities and phytochemistry

Article

Oct 2008
J ETHNOPHARMACOL

Fragrance Material Review on α-bisabolol

Article

Nov 2008
FOOD CHEM TOXICOL

A toxicologic and dermatologic review of alpha-bisabolol when used as a fragrance ingredient is presented.

Targeting apoptosis pathways in pancreatic cancer

Article

Nov 2010

Pancreatic cancer - here in particular pancreatic ductal adenocarcinoma (PDAC) - is still a highly therapy refractory disease. Amongst the mechanisms by which PDAC cells could escape any non-surgical therapy, anti-apoptotic protection seems to be the most relevant one. PDAC cells have acquired resistance to apoptotic stimuli such as death ligands (FasL, TRAIL) or anti-cancer drugs (gemcitabine) by a great number of molecular alterations either disrupting an apoptosis inducing signal or counteracting the execution of apoptosis. Thus, PDAC cells exhibit alterations in the EGFR/MAPK/Ras/raf1-, PI3K/Akt-, TRAIL/TRAF2-, or IKK/NF-κB pathway accompanied by deregulations in the expression of apoptosis regulators such as cIAP, Bcl2, XIAP or survivin. Along with protection against apoptosis, PDAC cells also overexpress histone deacetylases (HDACs) giving rise to epigenetic patterns of chemoresistance and to acetylation of other regulatory proteins, as well. With respect to the multitude of anti-apoptotic pathways, a great number of molecular targets might be of high potential in novel therapy strategies. Thus, natural compounds as well as novel synthetic drugs are considered to be used in single or combined therapy of PDAC. A number of proteasome and HDAC inhibitors or selective inhibitors of IKK, EGFR, Akt and mTOR have been widely explored in preclinical settings and clinical studies. Even though these early studies encouraged an application in a clinical setting, most of the trials have been rather disappointing yet. Thus, new molecular targets and novel concepts of combination therapies need to get access into clinical trials - either in neoadjuvant/adjuvant or in palliative treatments.

(−)-α-Bisabolol attenuates visceral nociception and inflammation in mice

Article

Sep 2010

The study examined the antiinflammatory and antinociceptive effects of the sesquiterpene (-)-α-bisabolol (BISA). The antiinflammatory effect was evaluated on acute models of dermatitis induced by Croton oil, arachidonic acid, phenol and capsaicin, respectively, in mouse ear. BISA inhibited the dermatitis induced by all noxious agents, except capsaicin. BISA was assessed in two established mouse models of visceral nociception. Mice were pretreated orally with BISA, and the pain-related behavioral responses to intraperitoneal cyclophosphamide or to intracolonic mustard oil were analyzed. BISA showed a dose-unrelated significant antinociception. Collectively, the results suggest that BISA may be an topical antiinflammatory and visceral antinociceptive agent.

In vivo effect of alpha-bisabolol, a nontoxic sesquiterpene alcohol, on the induction of spontaneous mammary tumors in HER-2/neu transgenic mice

Article

Jan 2010

Breast cancer represents the most commonly diagnosed invasive malignancy in pre- and postmenopausal women in both developed and underdeveloped countries. Taking into account that treatment options, including surgery, have not been able to deal with the growing incidence of breast malignancy, it is required to develop mechanism-based novel agents for its prevention. Wide interest in some natural compounds as anti-inflammatory agents and as alternative to the traditional medicines is increasing because they do not provoke any adverse effects and are effective in multiple organs. α-Bisabolol (BISA), a small oily sesquiterpene alcohol, was reported as chemopreventive agent in induced rat mammary carcinogenesis. The aim of the present study is to investigate the role played by two doses of BISA (via intramammary infusion) on the induction and development of mammary tumor in HER-2/neu transgenic mice as well as the BISA effect after tumor surgical resection. The main data show that (a) optimal dosage of BISA is 10 mg/mouse rather than 3.6 mg/mouse with no adverse effects (e.g., alopecia); (b) the number of the palpable tumor masses decreases in mice treated with 10 mg/mouse of BISA; (c) mice after surgical resection of the primary tumor and treatment with BISA (10 mg) are free from tumor for more weeks, after the surgical treatment; (d) using array analysis, some genes implicated in carcinogenesis mechanisms (NF-κBia, Map2k, Mapk14, and HER2/ neu), angiogenesis process (Fgf), and inhibition of apoptosis (Birc5) are differently regulated after BISA treatment, with a downregulation of the HER2/neu as well as of Fgf and Birc5 genes; (e) the NK cell cytotoxicity increases in tumor-treated mice, especially after the removal of the first tumor mass. Such effectiveness could be important to achieve goals for a possible combination of BISA to conventional therapies in breast cancer and to tumor surgical removal (adjuvant therapy), as suggested for other sesquiterpene analogs.

EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor

Article

Jul 2010

Synovial sarcoma is a high-grade soft tissue malignancy, for which current cytotoxic chemotherapies provide limited benefit. Although histone deacetylase (HDAC) inhibitors are known to suppress synovial sarcoma in vitro and in vivo, the exact mechanism is not clear. In this study, we report a central role of the transcription factor, early growth response-1 (EGR1), in the regulation of HDAC inhibitor-induced apoptotic cell death in synovial sarcoma. The SS18-SSX oncoprotein, characteristic of synovial sarcoma, maintains EGR1 expression at low levels, whereas it is significantly increased after HDAC inhibitor treatment. On the contrary, EGR1 knockdown leads to a decrease in HDAC inhibitor-induced apoptosis. Moreover, we find that under these conditions phosphatase and tensin homolog deleted in chromosome 10 (PTEN) is upregulated and this occurs through direct binding of EGR1 to an element upstream of the PTEN promoter. Using a combination of gain- and loss-of-function approaches, we show that EGR1 modulation of PTEN contributes to HDAC inhibitor-induced apoptosis in synovial sarcoma. Finally, restoration of EGR1 or PTEN expression is sufficient to induce synovial sarcoma cell death. Taken together, our findings indicate that SS18-SSX-mediated attenuation of an EGR1-PTEN network regulates synovial sarcoma cell survival, and that HDAC inhibitor-mediated apoptosis operates at least in part through reactivation of this pathway.

α-Bisabolol induces dose- and time-dependent apoptosis in HepG2 cells via a Fas- and mitochondrial-related pathway, involves p53 and NFκB

Article

Mar 2010

In this study, the apoptotic effect of alpha-bisabolol, a sesquiterpene, against human liver carcinoma cell line HepG2 was investigated. MTT assay showed alpha-bisabolol could effectively induce cytotoxicity in several human cancer cell lines (PC-3, Hela, ECA-109 and HepG2). The results of nuclei morphology examination, DNA fragmentation detection, flow cytometry analysis and cleavage of poly(ADP-ribose) polymerase and caspases indicated alpha-bisabolol might induce dose- and time-dependent apoptosis in HepG2 cells. Western blot data also showed a cascade activation of caspases-8,-9,-3 and promoted expression of Fas, implying caspase-8 might function as an upstream regulator, and the Fas-related pathway might be involved in this process. Preparation of mitochondrial/cytosol fraction followed with immunoblot analysis showed the release of chromosome c from mitochondria, down-regulated expression of Bcl-2 and translocation of Bax, Bak and Bid, suggesting the mitochondrial-related pathway might be involved in alpha-bisabolol-induced apoptosis either. Detection of accumulation of nuclear wild-type p53 and up-regulated expression of NFkappaB indicated these two key regulator with transcriptional decision-making function in various signaling pathways might also play a role in alpha-bisabolol-induced apoptosis in HepG2 cells.

Composition and biological activity of the essential oil from leaves of Plinia cerrocampanensis, a new source of α-bisabolol

Article

Dec 2009

The essential oil from fresh leaves of Plinia cerrocampanensis Barrie (Myrtaceae), obtained by hydrodistillation, was analysed by GC-FID and GC-MS. Forty components, representing more than 91% of the oil, were identified. Oxygenated sesquiterpenes represented the main fraction with alpha-bisabolol (42.8%) as the major constituent, making this plant a new and good source of this substance. Biological activity of the essential oil was evaluated against several bacterial and fungal strains as well as larvae from Aedes aegypti. The highest activity was found against Staphylococcus aureus, Pseudomonas aeruginosa, Microsporum gypseum, Trichophyton mentagrophytes and Trichophyton rubrum with MIC values from 32 to 125 microg/ml. The essential oil also showed potent inhibitory and bactericidal activities against three H. pylori strains, with MIC and MBC values of 62.5 microg/ml, and caused 100% mortality of A. aegypti larvae at a concentration of 500 microg/ml.

Gastroprotection of (-)-alpha-bisabolol on acute gastric mucosal lesions in mice: the possible involved pharmacological mechanisms

Article

Sep 2009
FUND CLIN PHARMACOL

(-)-Alpha-Bisabolol is an unsaturated, optically active sesquiterpene alcohol obtained by the direct distillation essential oil from plants such as Vanillosmopsis erythropappa and Matricaria chamomilla. (-)-Alpha-Bisabolol has generated considerable economic interest, since it possesses a delicate floral odor and has been shown to have anti-septic and anti-inflammatory activity. The aim of this work was to evaluate the gastroprotective action of (-)-alpha-bisabolol on ethanol and indomethacin-induced ulcer models in mice, and further investigate the pharmacological mechanisms involved in this action. The oral administration of (-)-alpha-bisabolol 100 and 200 mg/kg was able to protect the gastric mucosa from ethanol (0.2 mL/animal p.o.) and indomethacin-induced ulcer (20 mg/kg p.o.). Administration of L-NAME (10 mg/kg i.p.), glibenclamide (10 mg/kg i.p.) or indomethacin (10 mg/kg p.o.) was not able to revert the gastroprotection promoted by (-)-alpha-bisabolol 200 mg/kg on the ethanol-induced ulcer. Dosage of gastric reduced glutathione (GSH) levels showed that ethanol and indomethacin reduced the content of non-protein sulfhydryl (NP-SH) groups, while (-)-alpha-bisabolol significantly decreased the reduction of these levels on ulcer-induced mice, but not in mice without ulcer. In conclusion, gastroprotective effect on ethanol and indomethacin-induced ulcer promoted by (-)-alpha-bisabolol may be associated with an increase of gastric sulfydryl groups bioavailability leading to a reduction of gastric oxidative injury induced by ethanol and indomethacin.

Targeting PI3K signalling in cancer: Opportunities, challenges and limitations

Article

Sep 2009

Jeffrey A Engelman

There are ample genetic and laboratory studies that suggest the PI3K-Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K-Akt signalling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clinical development.

Involvement of mitochondrial permeability transition pore opening in ??-bisabolol induced apoptosis

Article

Jul 2009
FEBS J

Alpha-bisabolol is a natural monocyclic sesquiterpene alcohol. It has been used in cosmetics for hundreds of years because of its perceived skin-healing properties. Alpha-bisabolol is known to have anti-irritant, anti-inflammatory and antimicrobial properties. In precedent studies, we described how alpha-bisabolol exerts a selective pro-apoptotic action towards transformed cells [Cavalieri E et al. (2004) Biochem Biophys Res Commun 315, 589-594] and its uptake is mediated by lipid rafts on the plasma membrane [Darra E et al. (2008) Arch Biochem Biophys 476, 113-123]. In this study, we hypothesize that the intracellular target of alpha-bisabolol may be the mitochondrial permeability transition pore (mPTP). To evaluate this hypothesis, we used one transformed cell line (human glioma T67) in comparison with a nontransformed one (human fibroblasts). We assessed the effect of a specific mPTP inhibitor (cyclosporine A) on the toxic action of alpha-bisabolol. Results show that the alpha-bisabolol-induced decrease in oxygen consumption is abolished by the addition of cyclosporine A in T67 cells, indicating that alpha-bisabolol may target mPTP. The central role of mitochondria was also demonstrated by using galactose to force cells to a more aerobic metabolism. In this condition, we observed higher alpha-bisabolol toxicity. Furthermore, we studied the effect of alpha-bisabolol on isolated rat liver mitochondria. This study expands the notion of the specific action of alpha-bisabolol on transformed cells and suggests that it may act by disturbing the structure and function of the mPTP. Alpha-bisabolol toxicity is clearly related to its cellular uptake, which is higher in transformed cell lines.

α-bisabolol: Unexpected plant-derived weapon in the struggle against tumour survival?

Article

Jan 2008
Ital J Biochem

Despite enormous scientific and economic effort tumour still is one of the most terrible pathologies among human population all over the world. Products derived from the plant kingdom have often offered an opportunity to counteract or alleviate this illness. Here, we summarize the short story of the study of an extraordinary effect of one plant compound towards transformed cells derived from highly malignant tumours. Alpha-bisabolol, a sesquiterpene widely present in plants, selectively kills transformed cells by apoptosis without affecting the viability of normal cells. One of its intracellular targets seems to be situated on mitochondria and is possibly identified as the permeability transition pore, as judged from rapid mitochondrial membrane potential dissipation induced by alpha-bisabolol and the failure to kill cells in the presence of cyclosporine A. Preferential adsorption of alpha-bisabolol into lipid rafts, rich in tumour cells, may explain the selective action of this compounds towards tumour cells. Furthermore, Surface Plasmon Resonance analysis indicates that alpha-bisabolol directly interacts with Bid protein, a member of the Bcl2 family deeply involved in apoptosis, suggesting a possibility that Bid, or similar protein(s), may be involved in a putative intracellular transport system of alpha-bisabolol from plasma membrane to mitochondria. Experiments with animals indicate that alpha-bisabolol is not toxic and is accumulated, through blood flow, in every tissues examined. Further animal studies to test its effect are currently under way.

Antioxidant Activity of Bisabolol: Inhibitory Effects on Chemiluminescence of Human Neutrophil Bursts and Cell-Free Systems

Article

Jan 2009
PHARMACOLOGY

Human polymorphonuclear neutrophils (PMN), reactive oxygen species (ROS) and inflammatory reactions are closely interrelated, and increasing attention is being given to the search for new synthetic or natural antioxidant agents, capable of reducing ROS and consequent inflammation. It has been claimed that bisabolol (a monocyclic sesquiterpene alcohol) has an antioxidant/anti-inflammatory activity, but this has almost exclusively been investigated using chemical or biochemical tests. We studied the ability of bisabolol to interfere with ROS production (luminol-amplified chemiluminescence, LACL) during human PMN respiratory bursts induced by both corpusculate(Candida albicans)and soluble stimulants (N-formyl-methionyl-leucyl-phenylalanine, fMLP). LACL was also used to test cell-free systems (SIN-1 and H2O2/HOCl(-) systems) in order to investigate the presence of scavenging activity. After C. albicans stimulation, significant concentration-dependent LACL inhibition was observed at bisabolol concentrations ranging from 7.7 to 31 microg/ml; after the fMLP stimulus, significant LACL inhibition was observed at bisabolol concentrations ranging from 3.8 to 31 microg/ml. A similar effect was observed in the SIN-1 and H2O2/HOCl(-) systems. These findings draw the attention to the possible medical use of bisabolol as a means of improving the antioxidant network and restoring the redox balance by antagonising oxidative stress.

Pharmacological investigations with compounds of chamomile. II. New investigations on the antiphlogistic effects of (-)-??-bisabolol and bisabolol oxides

Article

Mar 1979

Chamomile extracts are mainly used because of their antiinflammatory action. Well–known are the antiphlogistic properties of chamazulene and (–)–alpha–bisabolol. So far the effects exerted by bisabolol oxides and by the synthetic racemic compound of bisabolol have been unclear. Therefore, it was not possible to determine the relevance of these substances in connection with the standardization of chamomile extracts and preparations. Experiments conducted in rat paw edema (carrageenin) have shown that the antiphlogistic effect exerted by (–)–alpha–bisabolol is considerably more marked than that of the bisabolol oxides A and B, and even more pronounced than that of bisabolon oxide and both (+)–alpha–bisabolol and (±)–alpha–bisabolol. Moreover, that antiphlogistic effect of (–)–alpha–bisabolol could be confirmed in a number of further experimental models, e. g. in adjuvant arthritis of the rat, in UV–erythema of the guinea pig and in yeast fever of the rat. In addition, (–)–alpha–bisabolol reduces the production of mucopolysaccharides in the cell cultures. As was evidenced in the experiments, the content of (–)–alpha–bisabolol is of relevance when assessing the antiphlogistic effectiveness of diamomile extracts and preparations. Therefore, chamomile preparations beside chamazulene should be standardized to (–)–alpha–bisabolol. A standardization of the bisabolol oxides does not seem to be reasonable in view of the considerably lower activity. For manufacturing chamomile extracts of antiphlogistic effectiveness, only such types of chamomile should be used which exhibit a high content of (–)–alpha–bisabolol besides a high content of chamazulene. And finally the experiments have shown that (–)–alpha–bisabolol has a considerably stronger effect than (+)–alpha–bisabolol and the synthetic racemic bisabolol. Therefore, it cannot be substituted for by these substances.

Cross-talk between phospholipase C and phosphoinositide 3-kinase signalling pathways

Article

Dec 1997

1321N1 astrocytoma cells have proved a valuable model system in which to study interactions between two major PtdIns (4,5) P2-utilizing signaling pathways, since they possess receptor populations which elicit independent activation of PI 3-kinase and a G-protein-dependent PLC respectively. Activation of PLC down-regulates PI 3-kinase by at least two mechanisms involving inhibition of IRS-1-associated PI 3-kinase and acute activation of a PtdIns (3,4,5) P3 5-phosphatase. PKB, which is an important early PI 3-kinase-dependent component of insulin signalling pathways, is also down-regulated by PLC-coupled agonists. The activation of PKB by insulin appears to involve a novel PtdIns (3,4,5) P3-dependent protein kinase, which we have named PDK1. The molecular mechanisms underlying PtdIns (3,4,5) P3-stimulated phosphorylation and activation of PKB by PDK1 are currently under investigation.

Anti-tumor efficacy of paclitaxel against human lung cancer xenografts

Article

Jan 1998
Jpn J Canc Res

We examined paclitaxel for anti-tumor activity against human lung cancer xenografts in nude mice and compared its efficacy with that of cisplatin, currently a key drug for lung cancer chemotherapy. Five non-small cell lung cancers (A549, NCI-H23, NCI-H226, NCI-H460 and NCI-H522) and 2 small cell lung cancers (DMS114 and DMS273) were chosen for this study, since these cell lines have been well characterized as regards in vitro and in vivo drug sensitivity. These cells were exposed to graded concentrations of paclitaxel (0.1 to 1000 nM) for 48 h. The 50% growth-inhibitory concentrations (GI50) for the cell lines ranged from 4 to 24 nM, which are much lower than the achievable peak plasma concentration of paclitaxel. In the in vivo study, 4 cell lines (A549, NCI-H23, NCI-H460, DMS-273) were grown as subcutaneous tumors xenografts in nude mice. Paclitaxel was given intravenously as consecutive daily injections for 5 days at the doses of 24 and 12 mg/kg/day. Against every xenograft, paclitaxel produced a statistically significant tumor growth inhibition compared to the saline control. Paclitaxel at 24 mg/kg/day was more effective than cisplatin at 3 mg/kg/day with the same dosing schedule as above, although the toxicity of paclitaxel was similar to or rather lower than that of cisplatin, in terms of body weight loss. In addition, paclitaxel showed potent activity against 2 other lung cancer xenografts (NCI-H226 and DMS114). Therefore, paclitaxel showed more effective, wider-spectrum anti-tumor activity than cisplatin in this panel of 6 lung cancer xenografts. These findings support the potential utility of paclitaxel in the treatment of human lung cancer.

Cantrell DAPhosphoinositide 3-kinase signaling pathways. J Cell Sci 114: 1439-1445

Article

May 2001

Doreen A Cantrell

Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3'-OH position of the inositol ring of inositol phospholipids, producing three lipid products: PtdIns(3)P, PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3). These lipids bind to the pleckstrin homology (PH) domains of proteins and control the activity and subcellular localisation of a diverse array of signal transduction molecules. Three major classes of signalling molecule are regulated by binding of D-3 phosphoinositides to PH domains: guanine-nucleotide-exchange proteins for Rho family GTPases, the TEC family tyrosine kinases such as BTK and ITK in B and T lymphocytes, respectively, and the AGC superfamily of serine/threonine protein kinases. These molecules are activated by a variety of extracellular stimuli and have been implicated in a wide range of cellular processes, including cell cycle progression, cell growth, cell motility, cell adhesion and cell survival.

Regulation of life and death by the zinc finger transcription factor Egr-1

Article

Dec 2002

The biosynthesis of the zinc finger transcription factor Egr-1 is stimulated by many extracellular signaling molecules including hormones, neurotransmitters, growth and differentiation factors, and cytotoxic metabolites. The 5'-flanking region of the Egr-1 gene contains genetic elements that are essential in connecting stimulation of the cells with enhanced transcription of the Egr-1 gene, and subsequently, transcription of Egr-1-responsive genes. Thus, Egr-1 links cellular signaling cascades with changes in the gene expression pattern. Many biological functions have been attributed to Egr-1. Here, we discuss evidence for Egr-1 control of cellular proliferation and programmed cell death.

Antitumor effects of α-bisabolol against pancreatic cancer

Abstract

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