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[alpha]-Bisabolol, a nontoxic natural compound, strongly induces apoptosis in glioma cells
Abstract
In this study, alpha-bisabolol, a sesquiterpene alcohol present in natural essential oil, was found to have a strong time- and dose-dependent cytotoxic effect on human and rat glioma cells. After 24 h of treatment with 2.5-3.5 microM alpha-bisabolol, the viability of these cells was reduced by 50% with respect to untreated cells. Furthermore, the viability of normal rat glial cells was not affected by treatment with alpha-bisabolol at the same concentrations as above. Glioma cells treated with high concentration of alpha-bisabolol (10 microM) resulted in a 100% cell death. Judging from hypo-G1 accumulation, poly(ADP-ribose) polymerase cleavage, and DNA ladder formation, the cytotoxicity triggered by alpha-bisabolol resulted from apoptosis induction. Moreover, the dissipation of mitochondrial-inner transmembrane potential and the release of cytochrome c from mitochondria indicated that, in these glioma cells, apoptosis occurred through an intrinsic pathway. As pointed out by the experimental results, alpha-bisabolol may be considered a novel compound able to inhibit glioma cell growth and survival.
... Chemical composition of essential oils of the aerial parts of I. viscosa collected in 10 stations in the North West of Algeria. oxidative stress (Su et al., 2015), b-caryophyllene, s-muurolol, a-cadinol and (2Z,6E)-farnesol exhibit cytotoxic activity against human colon, liver and lung cancer cells (Cavalieri et al., 2004). a-bisabolol was found to have a strong timeand dose-dependent cytotoxic effect on human and rat glioma cells (Cavalieri et al., 2004). ...
... oxidative stress (Su et al., 2015), b-caryophyllene, s-muurolol, a-cadinol and (2Z,6E)-farnesol exhibit cytotoxic activity against human colon, liver and lung cancer cells (Cavalieri et al., 2004). a-bisabolol was found to have a strong timeand dose-dependent cytotoxic effect on human and rat glioma cells (Cavalieri et al., 2004). ...
... The present molecular docking analysis MD simulations used to investigate new oxygenated sesquiterpene compound inhibitor of VEGF receptors. Previous studies have shown that (2Z,6E)-farnesol exhibited cytotoxic activity against human colon, liver and lung cancer cells (Cavalieri et al., 2004). ...
Angiogenes is therefore appears to be a complex phenomenon, finely regulated by various activators (pro-angiogenic factors) and inhibitors (anti-angiogenic factors). Among the pro-angiogenic factors, VEGF (Vascular Endothelial Growth Factor) seems to be one of the main players in tumor angiogenesis. It exerts its pro-angiogenic activity by attaching to the surface of receptors with tyrosine kinase activity (VEGFR). The aim of this research was the bioinformatical study of VEGFR inhibition by essential oils of the Inula viscosa.
Analyses of essential oils obtained by hydrodistillation from the aerial parts of the plant were performed using GC and GC/MS analysis. We used molecular modeling approaches as molecular mechanics to theoretical investigation VEGF receptors by natural inhibitors.
Nineteen compounds were identified, constituting 90.1-98.8% of the total essential oils. The main components of the plants were (E)-nerolidol (15.5–20.2 %), caryophyllene oxide (10.6–18.1%), (E)-Z-farnesyl acetone (13.2–25.1%) and (E)-β-farnesene (1.5–5.6%). Essential oil samples were clustered into two groups according to their chemical compositions. The molecular dynamics study was conducted for the best inhibitors. A few key residues were identified at the binding site of VEGFR. The Pharmacokinetics was justified by means of lipophilicity and high coefficient of skin permeability. The in silico evaluation of ADME revealed that L19 has high absorption. The essential oil of I. viscosa presents a significant variability. This study revealed that (E)-Z-Farnesylacetone is a functional inhibitor of VEGF activities and subsequently can be the best inhibitors candidate to be scrutinized in vivo and in vitro.
Communicated by Ramaswamy H. Sarma
... Exhibited cytotoxic effects and inhibited cell growth [205][206][207][208][209][210][211][212][213][214][215][216]. ...
... α-bisabolol was shown to induce cytotoxicity in transformed cells, while deprived of general toxicity in several mouse models [205]. The inhibitory effects of bisabolol have been shown in various types of cancer; non-small cell lung carcinoma cells (IC50 of 15 μM) [206], human and rat glioma cells (IC50 between 2.5-5 μM and 45 μM depending on the report) [207,208], B-chronic lymphocytic leukemia (IC50 42 μM) [209], as well as several other cancers such as primary lymphoid leukemias, pancreatic cancer cell lines, PC-3, HeLa, ECA-109 and HepG2 [210][211][212]. In vivo, 10 mg decreased the number of the palpable tumor masses in a mammary tumor model in HER-2/neu transgenic mice [218]. ...
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.
... Molecules 2020, 25, 1284 2 of 21 antimicrobial, antiviral, antimutagenic, anti-inflammatory, immunomodulatory, antiprotozoal, antifungal, and anticancer activities, [2][3][4][5]. Many Asteraceae plant species have a long history of ethnopharmacological use and are important for medicinal and pharmacological purposes at present [6][7][8][9][10]. ...
... Thymol, i.e., the main component of many aromatic and medicinal plants has been shown to have a stimulating effect on apoptosis and an inhibitory effect on cell growth in DBTRG-05MG human glioblastoma [63]. α-Bisabolol, which is a natural compound strongly inducing apoptosis in glioma cells [2], or β-Elemene, i.e., a natural plant drug obtained from Curcuma wenyujin inducing apoptosis in glioblastoma cells, exert promising anticancer effects against a broad spectrum of tumors [32,67]. Another example of molecules characterized by an anticancer effect on human glioblastoma cell line U87MG is aloe emodin, i.e., an anthraquinone compound present in the leaves of Aloe arborescens, and hispolon, which is a polyphenolic compound isolated from Phellinus linteus [68]. ...
Arnica montana L. is a medicinal plant with diverse biological activities commonly used in pharmacy and cosmetics. The attributes of A. montana are mainly related to the concentration and chemical composition of essential oils (EOs). Therefore, the objective of this study was to characterize the chemical composition of EOs derived from A. montana rhizomes and roots taking into account the age of the plants and to investigate the effect of the analyzed EOs on induction of apoptosis, necrosis, and autophagy in human glioblastoma multiforme T98G and anaplastic astrocytoma MOGGCCM cell lines. Rhizomes and roots of mountain arnica were harvested at the end of the third and fourth vegetation periods. The chemical composition of essential oils was determined with the GC–MS technique. Among the 37 components of the essential oil of A. montana, 2,5-dimethoxy-p-cymene (46.47%–60.31%), 2,6-diisopropylanisole (14.48%–23.10%), thymol methyl ether (5.31%–17.79%), p-methoxyheptanophenone (5.07%–9.65%), and α-isocomene (0.68%–2.87%), were detected in the rhizomes and roots of the three-year-old plants and in the rhizomes and roots of the four-year-old plants. The plant part (rhizome, root) and plant age can be determinants of the essential oil composition and, consequently, their biological activity. The induction of apoptosis (but not autophagy nor necrosis) at a level of 28.5%–32.3% is a promising result, for which 2,5-dimethoxy-p-cymene, 2,6-diisopropylanisole, thymol methyl ether, and p-methoxyheptanophenone are probably mainly responsible. The present study is the first report on the anticancer activities of essential oils from A. montana rhizomes and roots.
... It is widely utilized in cosmetic and pharmaceutical products due to its beneficial properties. α-Bisabolol also has anticancer influences against lung, pancreatic cancer, glioma, liver, and BCR-ABL + acute lymphoblastic leukemia (Wu et al. 2018;Seki et al. 2011;Uno et al. 2016;Murata et al. 2017;Cavalieri et al. 2004;Chen et al. 2010;Bonifacio et al. 2012). α-Bisabolol can suppress the growth of A549 cells through apoptosis which can act as a potential anti-cancer drug (Wu et al. 2018). ...
This study examined the safety and potential anti-lung cancer effects of combinations of phytol and α-bisabolol in Swiss albino mice. Both acute and subacute toxicity assessments showed that the combination of phytol and α-bisabolol is safe, with no adverse effects observed at higher concentrations. Hematological, biochemical, and histopathological tests showed no signs of toxicity in the heart, lungs, liver, spleen, and kidneys. The LD50 was greater than 2000 mg/kg, indicating a large safety margin. Histopathological analysis confirmed cancer induction in the B(a)P-induced group, which had significantly altered relative lung weights. Lung weight increased slightly pre and post-treatment, but histopathology showed normal alveolar epithelium. GSH and SOD levels increased significantly in B(a)P-exposed groups, indicating an adaptive antioxidant response. CAT levels increased significantly in the post-treatment group, demonstrating the role of combination of phytol and α-bisabolol in protecting against B(a)P-induced oxidative damage. Upregulation of Bax and downregulation of Bcl-2 caused a pro-apoptotic environment, suggesting a way to inhibit malignant cell survival. Modulation of caspase-3 and caspase-9 showed the complexity of carcinogen-induced apoptotic signaling. In conclusion, phytol and α-bisabolol were found to be safe and organ-protective, and demonstrated no acute or subacute toxicity. They modulate antioxidant defenses and apoptotic pathways, which may help prevent and treat lung cancer.
Graphical Abstract
... It is chemically an alcohol, therefore suffix 'ol' is added. It is a naturally 1 α-bisabolol Anticancer Induction of apoptosis through intrinsic pathway (Cavalieri et al. 2004) 2 ...
Historically natural compounds and their structural equivalents have significantly contributed to pharmacotherapy. Sesquiterpenes, the C15-terpenoids are the source of many modern pharmaceuticals and therapeutic medications. These are mostly present in higher plants as well as other living systems including fungi and marine animals. They exist naturally as hydrocarbons or in oxygenated forms like lactones, alcohols, acids, aldehydes, and ketones. The sesquiterpene alcohol; farnesol isolated from plants like Cymbopogon nardus, Polianthes tuberosa and Cyclamen persicum is a promising biomolecule having immense pharmacological properties. Various studies have shown its potential as an anti-inflammatory, antioxidant, cardioprotective, antihypertensive, antidiabetic, antianxiety, antimicrobial, hepatoprotective, and anticancer agent. This review summarizes the importance of sesquiterpenes with special reference to pharmacological properties of farnesol, the design and development of its nano formulations such as a nanoparticle, nanogels, nanocomposites, etc., and their efficacy in in vivo and in vitro models.
... Phytol is a diterpene alcohol found in plants such as green tea, and it has been shown to have anti-proliferative and apoptotic effects on various cancer cells, including lung cancer cells (Komiya et al. 1999;Thakor et al. 2017;Sakthivel et al. 2018). α-Bisabolol is a natural terpene alcohol found in chamomile and other plants, and it has been shown to have an anti-proliferation effect on A549 cells (Cavalieri et al. 2004;Murata et al. 2017;Wu et al. 2018). Furthermore, it has been suggested that the inclusion of α-bisabolol into PLGA NPs is a possible approach for creating novel antiinflammatory, antipyretic, and perhaps immune therapeutic substances (Marongiu et al. 2014). ...
This study explored the potential of poly-(lactic-co-glycolic) acid (PLGA) nanoparticles to enhance the effectiveness of anticancer treatments through combination therapy with phytol and α-bisabolol. The encapsulation efficiency of the nanoparticles was investigated, highlighting the role of ionic interactions between the drugs and the polymer. Characterization of PLGA-Phy+Bis nanoparticles was carried out using DLS with zeta potential and HR-TEM for size determination. Spectrophotometric measurements evaluated the encapsulation efficiency, loading efficiency, and in vitro drug release. FTIR analysis assessed the chemical interactions between PLGA and the drug actives, ensuring nanoparticle stability. GC-MS was employed to analyze the chemical composition of drug-loaded PLGA nanocarriers. Cytotoxicity was evaluated via the MTT assay, while Annexin V-FITC/PI staining and western blot analysis confirmed apoptotic cell death. Additionally, toxicity tests were performed on L-132 cells and in vivo zebrafish embryos. The study demonstrates high encapsulation efficiency of PLGA-Phy+Bis nanoparticles, which exhibit monodispersity and sizes of 189.3±5nm (DLS) and 268±54 nm (HR-TEM). Spectrophotometric analysis confirmed efficient drug encapsulation and release control. FTIR analysis revealed nanoparticle structural stability without chemical interactions. MTT assay results demonstrated the promising anticancer potential of all the three nanoparticle types (PLGA-Phy, PLGA-Bis, and PLGA-Phy+Bis) against lung cancer cells. Apoptosis was confirmed through Annexin V-FITC/PI staining and western blot analysis, which also revealed changes in Bax and Bcl-2 protein expression. Furthermore, the nanoparticles exhibited non-toxicity in L-132 cells and zebrafish embryo toxicity tests. PLGA-Phy+Bis nanoparticles exhibited efficient encapsulation, controlled release, and low toxicity. Apoptosis induction in A549 cells and non-toxicity in healthy cells highlight their clinical potential.
... Cells exposed to (-)-α-bisabolol for a time of 72 h demonstrated cellular damage at the concentrations of 100 μg/ml and 300 μg/ml. In previous studies, it was observed cytotoxic effect of (-)-α-bisabolol on several human cancer cell lines (Cavalieri et al. 2004(Cavalieri et al. , 2009Darra et al. 2008), and concluded that (-)-α-bisabolol-induced apoptosis in HepG2 cells in a dose-and time-dependent manner (Chen et al. 2010) and its uptake is mediated by lipid rafts on the plasma membrane (Darra et al. 2008). The effectiveness of (-)-α-bisabolol A as an agent against tumor cells is supported by its capability to act on different levels of cell regulation to elicit diverse concurrent signaling pathways, thereby neutralizing a variety of aberrant survival mechanisms leading to improved resistance in neoplastic cells (Rigo and Vinante 2016). ...
(–)-α-Bisabolol is a naturally occurring sesquiterpene found in the volatile oil of several plants from the Asteraceae family. This work aimed to evaluate the effect of (–)-α-bisabolol on survival rate and reactive oxygen species production in Drosophila melanogaster (Meigen, 1830), Drosophilidae, and the parameters of cytotoxicity and genotoxicity in peripheral human blood mononuclear and red blood cells. The effect of (–)-α-bisabolol, at the concentrations of 5, 25, and 250 μM, was evaluated using the survival rate of flies, reactive oxygen species production by 2′7′-dichlorodihydrofluorescein diacetate oxidation, and antioxidant activity modulation by analyzing the catalase activity. (–)-α-Bisabolol demonstrated no toxicity in the D. melanogaster model. Additionally, cell viability by the MTT (3-(4,5-dimethylthazolk-2-yl)-2,5-diphenyl tetrazolium bromide) assay, nuclear damage by the comet test in peripheral blood mononuclear cells, and the possible hemolytic activity of (–)-α-bisabolol at the concentrations of 1, 3, 10, 30, 100, and 300 μg/ml to the red blood cells obtained from peripheral blood. (–)-α-Bisabolol caused cytotoxicity and genotoxicity when peripheral blood mononuclear cells and red blood cells were exposed to higher concentrations and for a long period, decreasing cellular viability, causing damage at the nuclear level, and presenting hemolytic activity. Thus, these toxic effects emphasized the need for additional studies to characterize the pharmacological activity and toxicity of (–)-α-bisabolol.
... The α-bisabolol is an anti-inflammatory agent that also has analgesic, antimicrobial [34], and antineoplastic [35] properties. Although α-bisabolol exerted an effect regarding the improvement in wound healing [36], no statistically significant difference was found when compared to chlorhexidine alone. ...
The aim of the present study was to perform a systematic review of the literature regarding the effect of different mouthwashes on gingival healing after oral surgery in adults. Searches were conducted in seven databases (PubMed/MEDLINE, Cochrane Library, Clinical Trials Registry, Embase, LILACS, Web of Science, and Google Scholar) for relevant randomized controlled trials (RCTs) published up to April 2022. The selection of studies, data extraction, and risk of bias appraisal were performed independently by two reviewers, and a third researcher was consulted to resolve disagreements. Data syntheses were presented narratively for the different criteria of gingival wound healing. Among 4502 articles retrieved from the databases, 13 studies met the eligibility criteria and were included in the present review. Chlorhexidine was the most frequent mouthwash studied (eight studies) and was used in different concentrations and combinations. Cetylpyridinium chloride, H2 Ocean Sea Salt, Commiphora molmol 0.5%, chlorhexidine 0.12%, and essential oils reported better healing than a negative control. However, the uncertain risk of bias in most RCTs included in this review precludes definitive conclusions. Well-designed RCTs are therefore still needed in this area.
... In this study, we clarified the efficiency of cyclodextrin conjugated α-bisabolol (CD-BSB) in xenograft tumors using intravenous administration. The dissolution rate of αbisabolol is reported to be approximately 2.5% using ethanol, therefore it is not possible to administer this compound intravenously (15). Cyclodextrin is a substance, which is frequently used to encapsulate hydrophobic molecules to increase their solubility in water (10). ...
Background/aim:
α-Bisabolol is an essential oil component extracted from plants, such as chamomile. We have previously reported that α-bisabolol suppressed proliferation, invasion, and motility of pancreas cancer. Cyclodextrin improved the solubility of α-bisabolol, therefore it enabled to administer intravenously. The aim of this study was to clarify the effect of cyclodextrin conjugated α-bisabolol (CD-BSB) and the signals pathways associated with α-bisabolol for pancreatic cancer.
Materials and methods:
Human pancreatic cancer cell lines were treated with or without CD-BSB. Cytomorphology and apoptosis were assessed in these treated groups. In addition, several phosphorylated proteins were analyzed to clarify the signal pathway concerning CD-BSB. In subcutaneous xenograft model, tumor volume and Ki-67 expression were evaluated among Control (untreated), CD-BSB, or Gemcitabine (GEM).
Results:
CD-BSB significantly changed cytomorphology and induced apoptosis in pancreatic cancer cells. CD-BSB suppressed phosphorylation of focal adhesion kinase (FAK). In addition, pFAK 397 was inhibited by CD-BSB in a concentration-dependent manner in cancer cells. In the subcutaneous xenograft models, the tumor volume in the CD-BSB groups was lower than Control groups. Ki67-positive cells in CD-BSB treated group were lower than the GEM-treated groups.
Conclusion:
We clarified the efficiency of CD-BSB in xenograft tumor using intravenous administration. α-Bisabolol suppresses phosphorylation of FAK 397 and impairs cytoskeletal polymerization in a pancreatic cancer cell line. Further investigations are required to reveal the precise mechanisms of the antitumor effects of solubilized α-bisabolol to facilitate its clinical application. Our data indicate that solubilized α-bisabolol has therapeutic potential and could improve the prognosis of cancer patients.
... This process of cytotoxicity on glioma cells has been shown to be time and dose dependent. However, the advantage of this compound is at the same time its low toxic effect on animals, as shown in an animal experiment with a rat administered 120 mg/kg α-bisabolol, which showed no toxic effects after 24 h [57]. The low toxicity is also a reason why α-bisabolol is popular in cosmetics and perfumes [27]. ...
Essential oils have been used by indigenous peoples for medicinal purposes since ancient times. Their easy availability played an important role. Even today, essential oils are used in various fields—be it as aromatic substances in the food industry, as an aid in antibiotic therapy, in aromatherapy, in various household products or in cosmetics. The benefits they bring to the body and health are proven by many sources. Due to their complex composition, they offer properties that will be used more and more in the future. Synergistic effects of various components in an essential oil are also part of the reason for their effectiveness. Infectious diseases will always recur, so it is important to find active ingredients for different therapies or new research approaches. Essential oils extracted from the bark of trees have not been researched as extensively as from other plant components. Therefore, this review will focus on bringing together previous research on selected bark oils to provide an overview of barks that are economically, medicinally, and ethnopharmaceutically relevant. The bark oils described are Cinnamomum verum, Cedrelopsis grevei, Drypetes gossweileri, Cryptocarya massoy, Vanillosmopsis arborea and Cedrus deodara. Literature from various databases, such as Scifinder, Scopus, Google Scholar, and PubMed, among others, were used.
... Butanoic acid 2-methyl-4-methyl hexyl ester, methyl o-anisate, α-trans-bergamotene, α-humulene, elemicin, 1,10-diepi-cubenol, α-bisabolol and cuparenal could be singled out as identified only in the extract obtained by solventfree microwave extraction ( Table 1). Most of mentioned compounds were already proved as efficient larvicides and mosquito repellents (24,25), antioxidants and antimicrobial agents (26,27), anti-nociceptive and anti-inflammatory agents (28), cytotoxic on human and rat glioma cells (29). Above-mentioned advantages of solvent-free microwave extraction, together with the largest number of identified compounds and relative low operating costs, candidate this technique as a technique of choice for the extract from the fennel rhizome isolation. ...
The aim of the presented work was to compare the efficiency of innovative (solvent-free microwave extraction, microwave-assisted hydrodistillation and supercritical CO2 extraction) extraction techniques vs. conventional Clevenger hydrodistillation of essential oil (EO) from poorly studied fennel rhizome. It was found that innovative extraction techniques enhance the EOs/extracts isolation, save time and exclude solvents providing green ecologically technologies. Solvent-free microwave extraction proved to be the most efficient with limonene and (E)-anethole as dominant compounds in concentration of 12.34 ± 0.31 and 35.63 ± 1.51 mg/ml, respectively, as well as with the largest number of isolated and identified compounds. Primary aroma compounds were identified by two direct headspace techniques – static headspace extraction (HSS) and headspace solid phase microextraction (HS-SPME) confirming limonene and (E)-anethole as dominant compounds in primary aroma mixture with 53.7 ± 2.02% and 30.9 ± 1.43% (HSS) and 69.8 ± 2.80% and 13.1 ± 0.11% (HS-SPME), respectively.
... 2,3 In recent years, complementary and alternative medicines, consisting of natural products, have attracted attention due to their therapeutic efficacy, inexpensiveness and lower toxicity in comparison with modern chemotherapy drugs. Apparently, some potent natural compounds have the ability to induce apoptosis or cell death in different cancer cell lines either singly 4,5 or synergistically with modern drugs. 6,7 Honey, a natural healer, has been in use since ancient times due to its several beneficial health effects. ...
Colon cancer is the most prevalent cause of death from cancer across the globe. Although chemotherapy drugs are predominantly used, their toxicity always remains a cause of concern. As an alternative to synthetic drugs, natural compounds or nutraceuticals are comparatively less toxic. Honey is widely used across different cultures as an alternative form of medicine. It represents a prominent source of plant-phenolic compounds and there is demonstrable evidence of its anti-oxidant and anti-microbial activities. The aim of the present work was to investigate the anti-proliferative effect of some Indian honeys and analyze their mechanism of action in colon cancer. In order to establish the composition-activity relationship, we evaluated the bioactive components present in selected honey samples by GC-MS and HPLC analysis. Indian honey samples showed a significant inhibitory impact on cell growth by restricting cell proliferation, causing apoptosis, and restricting the cell cycle in the G2/M phase specifically for colon cancer cells. The apoptotic activities, as imparted by the honey samples, were established by Annexin V/PI staining, real-time PCR, and immunoblot analyses. The treated cells showed increased expressions of p53 and caspases 3, 8, and 9, thus indicating the involvement of both extrinsic and intrinsic apoptotic pathways. The honey samples were also found to inhibit the β-catenin/Wnt pathway. In the next phase of the study, the efficacy of these honey samples was evaluated in colon carcinoma induced SD-rats. Overall, these findings demonstrated that selected Indian honeys could be established as effective nutraceuticals for the prevention as well as cure of colon cancer.
... (500 mg in capsule): Short, and long term anxiolytic (generalized), and antidepressant through clinical trials for 8 weeks with 1500 mg daily dose [156,157,158,159], antidepressant on forced swimming test in mice, imipramine as a standard [160] 2.17.1.2. Other: a) Apigenin (23): Induces apoptosis through proteasomal degradation of HER2/neu in HER2/neuoverexpressing breast cancer cells via the phosphatidylinositol-3'-kinase/Akt-dependent pathway, upregulate of insulin-like growth factor binding protein-3 (leads to growth inhibition, and apoptosis of 22Rv1 xenograft in athymic nude mice) [161], antieczema, anti-osteoporosis [162], b) α-bisabolol (24): Promising inducer of apoptosis in highly malignant glioma cells [163], c) Chamomile oily E.: İn vitro anti-Helicobacter pylori activity, effective in stomach diseases, and peptic ulcer [164], phosphodiesterase inhibitory action, which leads to increased cAMP levels [165], d) Aq. E.: Because of selective estrogen receptor modulator activity, induce osteoblast differentiation, and have anti-cancer effects on breast cancer, and uterine cancer cells in vitro (concentrations of 10-100 μg/mL) [165], e) Hydroalcoholic E.: Decreasing spermatozoa count, and motility, spermatozoon tail length, serum testosterone level, and increase serum estradiol level [166], f) Aq.-MeOH E.: Antidiarrhoeal, antisecretory, and antispasmodic activities [167], g) EtOAc, Ch. fractions, PE., and Aq. ...
The increase of challenges in people's lives, daily problems as well as traumatic events could lead them to experience stress. Because of the side effects of current drugs, the recent medications are not sufficient to cure stress-related diseases; new approaches are needed in order to find more effective medications with fewer sideeffects. Ethnobotanical and ethnomedical research is increasingly recognized as a viable source of data and plausible pharmacological action of many plants. The review presents ethnobotanical information of the plants that have been used against stress-related diseases among local people of Turkey. In addition, a survey of the current literature on the topic aims to find new natural resources that will contribute to the development of drugs and bring them to the literature by scanning the scientific articles on the isolation and structure determination of the secondary metabolites of these medicinal plants, which have been already in use among the public for stressrelated disorders for centuries. This research is not only the first step in the research of promising new compounds against stress but it is also a presentation of data on medicinal plants of Turkey: Their medicinal parts, method of preparation, usage patterns and, if recorded, their dosages.
... BIS is a non-toxic plant derivative with an oral LD 50 of 13-14 g/kg of bodyweight in rodents [35,36] that, when administrated on its own at 25 mg/kg, did not cause any adverse effect and did not change any parameters evaluated in this study. The dosage has been selected based on published studies showing its efficacy in the attenuation of inflammation and oxidative stress in rodent models of nociception, myocardial infarction and neuronal damage [19,[37][38][39]. ...
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.
... Similar findings were reported by an earlier study which found that α-Bisabolol induced a cytotoxic effect on glioma cells with an inhibitory effect of 50% compared to untreated cells. The study also found that α-Bisabolol can mediate apoptosis by inducing cytochrome-C translocations from mitochondrial membrane [62]. ...
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.
... β-Bisabolol has not been investigated for any anti-inflammatory activities prior to this study, even though its isomer α-bisabolol has been extensively studied for anti-inflammatory and other biological activities. Activities associated with α-bisabolol include anti-inflammatory [49,54], anti-oxidant [70], and anti-cancer [71,72]. α-Bisabolol limits the secretion of pro-inflammatory mediators during chronic inflammation [49,54] and in this study, it was demonstrated that β-bisabolol, which differs from α-bisabolol by the position of a hydroxyl group (-OH), also has anti-inflammatory properties. ...
Natural α-bisabolol has been widely used in cosmetics and is sourced mainly from the stems of Candeia trees that have become endangered due to over exploitation. The in vitro anti-inflammatory activity of cotton gin trash (CGT) essential oil and the major terpenoid (β-bisabolol) purified from the oil were investigated against lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages as well as the 3t3 and HS27 fibroblast cell lines. Nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 8 (IL-8) were measured using Greiss reagent, enzyme-linked immunosorbent assay (ELISA), and cytokine bead array (CBA)-flow cytometry. Non-toxic concentrations of CGT oil and β-bisabolol (1.6–50.0 µg/mL) significantly inhibited the production of the inflammatory mediators in a dose-dependent manner. Maximal inhibition by β-bisabolol was 55.5% for NO, 62.3% for PGE2, and 45.3% for TNF-α production in RAW cells. β-Bisabolol induced a level of inhibition similar to an equal concentration of α-bisabolol (50.0 µg/mL), a known anti-inflammatory agent. These results suggest β-bisabolol exerts similar in vitro effects to known topical anti-inflammatory agents and could therefore be exploited for cosmetic and therapeutic uses. This is the first study to report the in vitro anti-inflammatory activity of β-bisabolol in CGT essential oil.
... The cytotoxicity of α-bisabolol has been reported against human and rat malignant glioma cancer cell lines. In α-bisabolol-treated cell lines, the rapid loss of inner transmembrane potential and an increase in cytochrome-c translocation indicate that α-bisabolol can trigger apoptosis through mitochondrial intrinsic pathway [145]. Another experimental study has confirmed the cytotoxic effect of α-bisabolol against several cancer cell lines. ...
The prominent cultivation of lemongrass (Cymbopogon spp.) relies on the pharmacological incentives of its essential oil. Lemongrass essential oil (LEO) carries a significant amount of numerous bioactive compounds, such as citral (mixture of geranial and neral), isoneral, isogeranial, geraniol, geranyl acetate, citronellal, citronellol, germacrene-D, and elemol, in addition to other bioactive compounds. These components confer various pharmacological actions to LEO, including antifungal, antibacterial, antiviral, anticancer, and antioxidant properties. These LEO attributes are commercially exploited in the pharmaceutical, cosmetics, and food preservations industries. Furthermore, the application of LEO in the treatment of cancer opens a new vista in the field of therapeutics. Although different LEO components have shown promising anticancer activities in vitro, their effects have not yet been assessed in the human system. Hence, further studies on the anticancer mechanisms conferred by LEO components are required. The present review intends to provide a timely discussion on the relevance of LEO in combating cancer and sustaining human healthcare, as well as in food industry applications.
... The oily sesquiterpene alcohol, α-Bisabolol, as a promising anti-tumoral compound [24], has shown to induce cell death through the mitochondrial pathway in human malignant glioma cell lines. Interestingly, this compound did not show toxicity to the normal glial cells [31]. α-bisabolol also has shown to inhibit activation of Akt along with the expression of PI3K, PDK1, and mTORC2, which are the upstream signals of Akt [32]. ...
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.
... intrinsic pathway [143]. Another experimental study has confirmed the cytotoxic effect of α-bisabolol against several cancer cell lines. ...
The prominent cultivation of lemongrass relies on the pharmacological incentives of its essential oil. The lemongrass essential oil (LEO) has a significant amount of citral (mixture of geranial and neral), isoneral, isogeranial, geraniol, geranyl acetate, citronellal, citronellol, germacrene-D, and elemol in addition to numerous other bioactive compounds. These components confer various medicinal activities to LEO including antifungal, antibacterial, antiviral, anticancer, and antioxidant properties. These attributes are commercially exploited in pharmaceutical, cosmetics, and food preservations industries. Furthermore, the employment of LEO in the treatment of cancer opens a new vista in the field of therapeutics. Although different LEO components have shown promising anticancer activities in vitro, these effects have not been assessed yet in humans. Further studies on the anticancer mechanisms exerted by lemongrass components are required. The present review intends to provide a timely discussion on the relevance of lemongrass extracts in cancer and health treatment, and in food industry applications.
... However, doxorubicin has also been reported to induce necrosis [54,62]. Furthermore, it has been described that alpha-bisabolol can promote cytochrome C release from the mitochondria to the cytosol, caspase-3 activation, and reduction in the ratio of BCL-2/Bax, and pro-apoptotic pathways in several cancer cell lines [14,15,65]. ...
Glioblastoma (GB) is a histological and genetically heterogeneous brain tumor that is highly proliferative and vascularized. The prognosis is poor with currently available treatment. In this study, we evaluated the cytotoxicity and antiangiogenic activity of doxorubicin-loaded-chitosan-coated-arginylglycylaspartic acid-functionalized-poly(ε-caprolactone)-alpha bisabolol-LNC (AB-DOX-LNC-L-C-RGD). The nanoformulation was prepared by self-assembling followed by interfacial reactions, physicochemically characterized and evaluated in vitro against GB cell lines (U87MG and U138MG) and in vivo using the chicken chorioallantoic membrane assay (CAM). Spherical shape nanocapsules had a hydrodynamic mean diameter of 138 nm, zeta potential of +13.4 mV, doxorubicin encapsulation of 65%, and RGD conjugation of 92%. After 24 h of treatment (U87MG and U138MG), the median inhibition concentrations (IC50) were 520 and 490 nmol L⁻¹ doxorubicin-equivalent concentrations, respectively. The treatment induced antiproliferative activity with S-phase cell-cycle arrest and apoptosis in the GB cells. Furthermore, after 48 h of exposure, evaluation of antiangiogenic activity (CAM) showed that the relative vessel growth following treatment with the nanocapsules was 5.4 times lower than that with the control treatment. The results support the therapeutic potential of the nanoformulation against GB and, thereby, pave the way for future preclinical studies.
... The oily sesquiterpene alcohol, α-Bisabolol, as a promising anti-tumoral compound [24], has shown to induce cell death through the mitochondrial pathway in human malignant glioma cell lines. Interestingly, this compound did not show toxicity to the normal glial cells [31]. α-bisabolol also has shown to inhibit activation of Akt along with the expression of PI3K, PDK1, and mTORC2, which are the upstream signals of Akt [32]. ...
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.
... BSB is also an ingredient in several perfumes, soaps, detergents, and personal hygiene products [26]. Recently, BSB was shown to be effective against various tumors, such as pancreatic cancer [27], liver carcinoma, acute leukemia [28][29][30][31], and glioma [32]. ...
Cystic echinococcosis (CE) remains an important challenge both in humans and animals. There is no safe and suitable remedy for CE, so the discovery of new compounds with promising scolicidal effects, particularly from herbal sources, is of great importance for therapeutic uses in the treatment and prevention of CE reappearance. Sesquiterpenes are C15 organic compounds made up of three isoprene units and mostly occurring as fragrant components of essential oils. They are of economic importance for the cosmetic and pharmaceutical industry, and recently attracted the attention of the scientific community for their remarkable parasiticidal properties. In the present study, we have focused on three known sesquiterpenes, isofuranodiene (IFD), α-bisabolol (BSB), and farnesol (FOH), as important phytoconstituents of the essential oils of wild celery (Smyrnium olusatrum), chamomile (Matricaria chamomilla), and acacia farnese (Vachellia farnesiana), respectively. Protoscoleces were recovered from fertile hydatid cysts and were exposed to different concentrations of the three tested compounds for different exposure times. The viability of protoscoleces was confirmed by 0.1% eosin staining. Results of scolicidal activity evaluations showed that IFD possessed the best effect against Echinococcus granulosus protoscoleces (LC50 and LC90 values of 8.87 and 25.48 µg/mL, respectively), followed by BSB (LC50 of 103.2 µg/mL) and FOH (LC50 of 113.68 µg/mL). The overall toxicity of IFD differed significantly from those of FOH and BSB, while there was no significant difference in toxicity between the latter compounds (p > 0.05). The present study showed that IFD seems to be a promising scolicidal agent and can be further tested to become a candidate for CE treatment.
... We found more therapeutically interesting structures upon doing our analyses. For instance, 10-epi-γ-eudesmol is highly effective against melanoma and column carcinoma cells proliferation [108]; β-eudesmol is antihepatotoxic, antiangiogenic, and antitumor [109][110][111]; α-eudesmol induces apoptosis [112]; bulnesol possesses antitussive and expectorant activity [113]; α-bisabolol induces apoptosis of malignant tumor cells, cytotoxicity, and antigenotoxicity [114][115][116][117][118]; guaiol is an anti-inflammatory, antimicrobial, and analgesic terpenoid [70,71]; and α-humulene acts as an appetite suppressant, antibacterial, and antitumor agent and is an effective anti-inflammatory and analgesic sesquiterpene [73,119]. Monoterpenoid constituents have antioxidant, anti-inflammatory, and estrogenic effects, and these activities are also relevant to current Alzheimer's disease therapy. ...
Cannabis sativa plant has not only cannabinoids as crucial compounds but also the other compounds that play important role as synergistic and/or entourage compound. Cannabis/hemp plant materials and essential oils were analyzed with the help of gas chromatography/mass spectrometry detector for the content of terpenes and terpenoids. The main terpenes/terpenoids and their abundance in the samples were evaluated. Results of this study will be helpful in the next evaluation of these compound in mixture with cannabinoids and their importance in medical treatment.
... It has proved its effect when tested on many cancer diseases of human like colon cancer, gastric cancer, breast cancer etc. α-β isabolol is a major alcohol found in essential oils which is found to be nontoxic in normal cells of animal models. It is a promising inducer of apoptosis in highly malignant glioma cells (Carnesecchi et al. 2004;Cavalieri et al. 2004;Wu et al. 2004). Monoterpene alcohols like Geraniol showed reduction in the amounts of thymidylate synthase and thymidine kinase expression. ...
Essential oils (EOs) are natural products obtained from different parts of a plant, such as flower, leaves, stems, fruits, seeds, roots, barks, or resin. It represents an important part of traditional pharmacopeia practices in healing of human ailments. It is used as raw materials in cosmetics, spices, foods, perfumes, and in treatment of several health disorders. There are several methods for extracting EOs from plants. They are the methods like hydro-distillation, steam distillation, hydro diffusion and cold pressing to name a few. The use of EOs as antimicrobial and pharmaceutical agents for curing various diseases has gained a considerable attraction of researchers in recent times. The complex mixture of EOs and their constituents have been reported to inhibit human pathogens, insects, and another harmful organism. The current review focusses on the chemical bioactive components of EOs, methods of extraction, chemical constituent, different plants as source of extraction and its application towards the treatment of various diseases in our day to day life, in vivo validation of essential oil, nanoformulation of essential oils.
... Bisabolol (levomenol), a well-known monocyclic unsaturated sesquiterpene alcohol, is widely used in pharmaceutical and cosmetic preparations due to its antiinflammatory, antibacterial, antiseptic, skin-soothing and moisturizing properties, as well as its low toxicity [46][47][48][49] . Bisabolol has also been reported to be a promising inducer of apoptosis in highly malignant Glioma cells [49,50] . ...
This study was carried out to determine the fatty acid composition of secondary metabolites produced by a lipid-producing endophytic fungus Pseudofusicoccum sp. The fungus was isolated from the leaves of Annona muricata growing in Ifite Dunu, Anambra State, SouthEast Nigeria. Solid state fermentation was carried out using rice medium and the metabolites were extracted with ethyl acetate. The crude ethyl acetate extract was subjected to vacuum liquid chromatography (VLC), and the fatty acid profiles of the resulting oleaginous fractions were analyzed using gas chromatography-mass spectroscopy (GC-MS). GC-MS analysis of the fractions revealed the abundance of both saturated and unsaturated fatty acids. Ethyl palmitate (17.31%) was the most abundant compound in F1; while bisabolol (11.45%), ethyl oleate (12.73%), and palmitic acid (22.22%) were predominant in F2. These compounds have been reported to show beneficial biological properties with potentials for pharmaceutical and industrial applications.
... The sesquiterpene α-bisabolol, from the essential oil of chamomile (Matricaria chamomilla), was shown to induce cell death in cancerous gliomas (Cavalieri et al. 2004). Malignant cells in the colon with enhanced 5-FU cytotoxicity were shown to be coincident with decreased activity and manifestation levels of thymidine kinase (TK) and thymidylate synthase (TS), an event which was shown to positively mediated by the monoterpene alcohol: Geraniol (Agarwal et al. 2008;Bajpai et al. 2009;Carnesecchi et al. 2002;Mans et al. 1999). ...
Essential oils, secreted by plants, are primarily meant for various physiological, ecological, and defense activities. These oils belong to various classes, i.e., isolates of fatty acids, isoprenoids, and phenolic complexes, and can be secreted by various organs of plants. The essential oil market globally has been predicted to grow at a compound annual growth rate (CAGR) of ~8–10%, and reach a staggering figure in excess of USD ten billion in the next 5 years or so. However, the challenge lies in commercial production, keeping pace with the demand, since their natural production in plants is in considerably low quantities, which depends on ecological conditions and growth stages of the plant. Although several investigations exist in the literature, there is a pressing need for a systematic review of the recent updates, particularly concerning the strategies that facilitate the manufacturing of such indispensable oils. The current chapter focuses on various facets of essential oil production, the associated challenges, and the promise of genetic alteration techniques for enhanced essential oil production. Several distinct perspectives have been considered, such as different sources and mechanisms of essential oil biomanufacturing, including their role in plant defense, the array of isolation procedures, and their wide ranges of beneficial attributes, particularly catering to the therapeutic potential, and challenges and metabolic engineering characteristics. A crucial feature of the current chapter is a critical review, underlining these aspects with a case study, using the commercially valuable sandalwood oil as an example, to emphasize the genetic modification strategies for enhancing sandalwood oil.
... Additionally, the dissipation of mitochondrial-inner transmembrane potential along with the discharge of cytochrome C from the mitochondria, in these glioma cells indicated that apoptosis took place through an intrinsic pathway. Moreover, α-bisabolol was found to be non-toxic given that the viability of normal rat glial cells was not affected (Cavalieri et al., 2004). Moreover, Hassan et al. (2018) demonstrated from their findings that Thymus bovei Benth. ...
Background
Essential oils (EOs) have remained in the limelight of the scientific community due their versatility coupled with consumers increasing demand for natural, safe and effective health products. Besides, its applications in the food, pharmaceutical, agricultural and textile industries amongst others have consolidated its popularity.
Scope and approach
EOs are rich sources of pharmacologically active phytoconstituents which justifies their health and industrial applications. Despite their wide applications, their low aqueous solubility, high volatility and sensitivity to light, temperature and oxygen compromises the exploration of their abounding benefits. Hence, this paper focuses on disseminating the chemistry, pharmacology, modes of action as well as the applications of EOs in various industries. Additionally, it focuses on the factors affecting their yield and composition as well as novel methods (micro-/nano-technology) that can be employed to optimize their effects.
Key findings and conclusions: The pharmacological properties (anti: microbial; oxidant; hyperpigmentation; diabetic; microbial; viral; and cancer properties as well as the cardio-, hepato- and neuro-protective) of EOs have been validated through various studies and their corresponding mechanisms of action have been reported in this paper. Notably, their antimicrobial and antioxidant attributes have enabled their exploration in active packagings whereby they extend the shelf life alongside maintaining food quality. On the other hand, their encapsulation in nanodelivery sytems permits to target and modulate their release thereby enhancing their pharmacological potential for biomedical aplications. In addition to imparting fragrance, they serve as antimicrobials in fabrics in textile industry. In agriculture, their biocidal effects makes them effective eco-friendly pesticides.
... Because of this feature it is widely used for flavoring liquids and foods and is also present in preparations of makeup, eye creams, moisturizers, antiperspirants, cleansers, and sunscreens [17,18]. It also presents important biological and pharmacological properties, such as anti-inflammatory, antiparasitic, anti-tumor, antiirritant, antiallergic, antifungal, and antibacterial activity [19,[20][21][22]. ...
Efflux pumps are proteins present in the plasma membrane of bacteria, which transport antibiotics and other compounds into the extracellular medium, conferring resistance. The discovery of natural efflux pump inhibitors is a promising alternative. α-Bisabolol is a sesquiterpene isolated from several plants such as Matricaria chamomilla L. and has important properties such as antibacterial and anti-inflammatory activity. Currently, the formation of inclusion complexes with β-Cyclodextrin has been used for improving the physicochemical characteristics of the host molecule. This study evaluated the effect of α-Bisabolol, in isolation and in complexation with β-Cyclodextrin, as TetK and NorA efflux pump inhibitors in Staphylococcus aureus strains. The minimum inhibitory concentration (MIC) was determined. Subsequently, inhibitory activity over the pumps was observed by an MIC reduction for the antibiotics, by using subinhibitory concentrations (MIC/8) in combination with tetracycline and norfloxacin. The MIC of the compounds was ≥1024 μg/mL. α-Bisabolol potentiated the action of tetracycline and reduced the MIC of norfloxacin to a clinically relevant concentration. The complexed substance showed synergism however, the effect of the isolated α-Bisabolol was superior to the complex. These results indicate α-Bisabolol is a potential substance to be used as an efflux pump inhibitor.
... In addition, several preclinical studies from our group and others revealed that BSB exerts pleiotropic effects against a wide range of transformed cells, eventually leading to bioenergy dissipation, membrane permeabilization, and regulated cell death (RCD) [5][6][7][8][9][10][11] . Because of its low toxicity at the therapeutic dosages, easy administration route and opportunity for synergism 5,11 , BSB has already been tested in animal models 11 and proposed as a novel antineoplastic agent for treating acute lymphoblastic leukemia 5,8 , chronic myeloid and lymphocytic leukemias 5,7 , malignant gliomas 9 , and pancreatic carcinomas 11 . ...
α-Bisabolol (BSB) is a plant-derived sesquiterpene alcohol able to trigger regulated cell death in transformed cells, while deprived of the general toxicity in several mouse models. Here, we investigated the involvement of lysosomal and mitochondrial compartments in the cytotoxic effects of BSB, with a specific focus on the BH3-only activator protein BID. We found that BSB particularly accumulated in cancer cell lines, displaying a higher amount of lipid rafts as compared to normal blood cells. By means of western blotting and microscopy techniques, we documented rapid BSB-induced BID translocation to lysosomes and mitochondria, both of them becoming dysfunctional. Lysosomal membranes were permeabilized, thus blocking the cytoprotective autophagic flux and provoking cathepsin B leakage into the cytosol. Multiple flow cytometry-based experiments demonstrated the loss of mitochondrial membrane potential due to pore formation across the lipid bilayer. These parallel events converged on neoplastic cell death, an outcome significantly prevented by BID knockdown. Therefore, BSB promoted BID redistribution to the cell death executioner organelles, which in turn activated anti-autophagic and proapoptotic mechanisms. This is an example of how xenohormesis can be exploited to modulate basic cellular programs in cancer.
... There are only a few studies on the effects of EO or their components on glioma cells. Those with the most spectacular effects include α-bisabolol, i.e., a nontoxic natural compound that strongly induces apoptosis in glioma cells [34]. Thymol has been shown to have an inhibitory effect on apoptosis and cell growth in DBTRG-05MG human glioblastoma [59]. ...
Mountain arnica Arnica montana L. is a source of several metabolite classes with diverse biological activities. The chemical composition of essential oil and its major volatile components in arnica may vary depending on the geographical region, environmental factors, and plant organ. The objective of this study was to characterize the chemical composition of essential oil derived from A. montana achenes and to investigate its effect on induction of apoptosis and autophagy in human anaplastic astrocytoma MOGGCCM and glioblastoma multiforme T98G cell lines. The chemical composition of essential oil extracted from the achenes was examined with the use of Gas Chromatography–Mass Spectrometry GC-MS. Only 16 components of the essential oil obtained from the achenes of 3-year-old plants and 18 components in the essential oil obtained from the achenes of 4-year-old plants constituted ca. 94.14% and 96.38% of the total EO content, respectively. The main components in the EO from the arnica achenes were 2,5-dimethoxy-p-cymene (39.54 and 44.65%), cumene (13.24 and 10.71%), thymol methyl ether (8.66 and 8.63%), 2,6-diisopropylanisole (8.55 and 8.41%), decanal (7.31 and 6.28%), and 1,2,2,3-tetramethylcyclopent-3-enol (4.33 and 2.94%) in the 3- and 4-year-old plants, respectively. The essential oils were found to exert an anticancer effect by induction of cell death in anaplastic astrocytoma and glioblastoma multiforme cells. The induction of apoptosis at a level of 25.7–32.7% facilitates the use of this secondary metabolite in further studies focused on the development of glioma therapy in the future. Probably, this component plays a key role in the anticancer activity against the MOGGCCM and T98G cell lines. The present study is the first report on the composition and anticancer activities of essential oil from A. montana achenes, and further studies are required to explore its potential for future medicinal purposes.
Cancer, a complex global health burden, necessitates the development of innovative therapeutic strategies. While chemotherapy remains the primary treatment approach, its severe side effects and chemoresistance drive the search for...
Aromatherapy is a medical practice that uses aromatic compounds or essential oils to influence mood and health. Essential oils used in aromatherapy are created from a wide variety of medicinal plants, flowers, herbs, roots, and trees that are found all over the world and have significant, well-documented benefits on enhancing physical, emotional, and spiritual wellbeing.
This book is a comprehensive reference on aromatic compounds present in essential oils and their therapeutic use. Starting from fundamentals of essential oil biosynthesis the book guides the reader through their basic biochemistry, toxicology, profiling, blending and clinical applications. The concluding chapters also present focused information about the therapeutic effects of essential oils on specific physiological systems, plant sources, skin treatment and cancer therapeutics.
The combination of basic and applied knowledge will provide readers with all the necessary information for understanding how to develop preclinical formulations and standard clinical therapies with essential oils. This is an essential reference for anyone interested in aromatherapy and the science of essential oils.
Breast cancer is a highly feared form of cancer that predominantly affects women. In pursuing effective treatments, herbal medicine has garnered attention as a viable resource. It holds promise as an alternative approach for managing and combating breast cancer. The primary objective of the research was to explore how α-Bisabolol hinders the growth of MCF-7 human breast cancer cells and decipher its molecular mechanisms of reducing cell proliferation and promoting apoptosis. In the experiment, cultured MCF-7 cells were divided into four distinct groups: The first group functioned as the control, whereas the second, third, and fourth groups received separate treatments of α-Bisabolol at varying concentrations. After allowing the cells to incubate for a 24-hour, we examined them to assess any alterations in their morphology after applying α-Bisabolol. This treatment led to the suppression of cell growth, an elevation in the generation of reactive oxygen species (ROS) and the initiation of apoptosis. Furthermore, examination through western blot and real-time PCR unveiled that cell treated with α-Bisabolol exhibited reduced levels of the cell survival gene Bcl-2, alongside elevated levels of the pro-apoptotic genes Bax, Bad, Caspase-3, Caspase-9, and cytochrome c. Meanwhile, NF-κB, p-PI3K, and p-Akt proteins were downregulated in α-Bisabolol treated cells. These results suggest that α-Bisabolol diminishes the cell viability of MCF-7 cells and triggers cellular apoptosis through both the mitochondrial pathway and the NF-κB/Akt/PI3K signaling pathways.
Alzheimer's disease (AD) is one of the major devastating neurodegenerative disorders associated with the gradual decline of an individual's memory, cognition, and ability to carry out day‐to‐day activities. In the present study, the neuroprotective ability of α‐bisabolol β‐ d ‐fucopyranoside (ABFP) was assessed via measurement of antioxidant parameters like lipid peroxidation, glutathione peroxidation, glutathione, protein carbonyl content assays, and caspase‐3 activity estimation. Moreover, the acute toxicity of ABFP was estimated in the zebrafish larval model. The results showed that ABFP exhibits little to no toxicity at lower concentrations in the acute toxicity test. ABFP‐pretreated and scopolamine‐exposed fish exhibited more exploratory behavior in the behavior assay than scopolamine‐only induced groups. Additionally, the results of antioxidant enzyme assays revealed reduced oxidative stress and damage in ABFP‐treated fish, while enzyme activity experiments carried out with brain homogenate from ABFP‐treated fish showed decreased acetylcholinesterase enzyme activity. Overall, it can be concluded that ABFP has the potential to be a promising agent for the treatment of AD in the future.
There are millions of plants worldwide, yet most of them have not been investigated for their medicinal properties. The development and recognition of medicinal plants increase at an exponential rate in industrialized and developing nations, resulting in research works on medicinal plants congregating toward therapeutic needs. The remarkable diversity of both chemical structure and biological activities of naturally occurring secondary metabolites, the utility of novel bioactive natural compounds as biochemical probes, the development of novel and sensitive techniques to detect biologically active natural products paved way to improved approaches to isolate, purify, and structurally characterize these bioactive constituents, and advancement in solving the demand for supply of complex natural products.The main focus of this review is to highlight the potential benefits of the Lamiaceae plant derived from multiple compounds and the importance of phytochemicals for the development of biocompatible therapeutics. In addition, this review focuses on problems encountered in medicinal plant research and discusses future directions. This review suggests that conservation strategies and resource management should be considered for sustainable utilization of medicinal plants. This review also recommends that the medicinal plant research should focus on tap plant components of Orthosiphon and deliver the most beneficial health products.KeywordsLamiaceae
Orthosiphon
Natural productsNatural drugsConservationSustainable utilization
Semambu (C. surinamense L) plant is a shrub plant that is easy to find. Several terpenoid compounds have been isolated from this plant, previous studies have shown cytotoxic activity of terpenoid class compounds. Terpenoid compounds in a plant are mostly found in essential oils (monoterpenes and sesquiterpenes). So far, there has been no report on the cytotoxic potential of essential oils from the leaves of this plant. It is necessary to isolate the essential oils from C. surinamense L leaves and test their cytotoxic potential. Isolation of essential oil of C. surinamense L leaves was carried out by hydrodistillation method, the oil was obtained in the form of a light yellow liquid with a specific gravity of 0.968 g/mL. Analysis of chemical components with Gas Chromatography-Mass-Spectrometry (GC-MS) through comparison of data from the National Institute of Standards and Technologies (NIST) found that there were 55 compounds (monoterpene and sesquiterpene groups) with six main compounds, namely β-caryophyllene (30.4%), β-sesquiphellandrene (8.46%), 3 carene (8.16%), α-bisabolene (4.05%), α-humulene (4.0%), and epi- bicyclosesquiphellandrene (4.0%). The potential cytotoxic test of essential oil from isolation showed highly cytotoxic activity with the Brine Shrimp Lethality Test (BSLT) method against Artemia salina L shrimp larvae with LC50 value of 0.9261 μg/mL and Microculture tetrazolium test (MTT) method against T47D breast cancer cells and HeLa cervix with IC50 values of 12.72 μg/mL and 30.14 μg/mL.
The cyclization of farnesyl diphosphate (FPP) into highly strained polycyclic sesquiterpenes is challenging. We here determined the crystal structures of three sesquiterpene synthases (STSs, namely, BcBOT2, DbPROS, and CLM1) catalyzing the biosynthesis of the tricyclic sesquiterpenes presilphiperfolan-8β-ol (1), Δ6-protoilludene (2), and longiborneol (3). All three STS structures contain a substrate mimic, the benzyltriethylammonium cation (BTAC), in their active sites, providing ideal templates for quantum mechanics/molecular mechanics (QM/MM) analyses toward their catalytic mechanisms. The QM/MM-based molecular dynamics (MD) simulations revealed the cascade reactions toward the enzyme products, and different key active site residues that play important roles in stabilizing reactive carbocation intermediates along the three pathways. Site-directed mutagenesis experiments confirmed the roles of these key residues and concomitantly resulted in 17 shunt products (4-20). Isotopic labeling experiments addressed the key hydride and methyl migrations toward the main and several shunt products. These combined methods provided deep insights into the catalytic mechanisms of the three STSs and demonstrated how the chemical space of STSs can rationally be expanded, which may facilitate applications in synthetic biology approaches toward pharmaceutical and perfumery agents.
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.
Brain tumours have unresolved challenges that include delay prognosis and lower patient survival rate. The increased understanding of the molecular pathways underlying cancer progression has aided in developing various anticancer medications. Brain cancer is the most malignant and invasive type of cancer, with several subtypes. According to the WHO, they are classified as ependymal tumours, chordomas, gangliocytomas, medulloblastomas, oligodendroglial tumours, diffuse astrocytomas, and other astrocytic tumours on the basis of their heterogeneity and molecular mechanisms. The present study is based on the most recent research trends, emphasising glioblastoma cells classified as astrocytoma. Brain cancer treatment is hindered by the failure of drugs to cross the blood–brain barrier (BBB), which is highly impregnableto foreign molecule entry. Moreover, currently available medications frequently fail to cross the BBB, whereas chemotherapy and radiotherapy are too expensive to be afforded by an average incomeperson and have many associated side effects. When compared to our current understanding of molecularly targeted chemotherapeutic agents, it appears that investigating the efficacy of specific phytochemicals in cancer treatment may be beneficial. Plants and their derivatives are game changers because they are efficacious, affordable, environmentally friendly, faster, and less toxic for the treatment of benign and malignant tumours. Over the past few years, nanotechnology has made a steady progress in diagnosing and treating cancers, particularly brain tumours. This article discusses the effects of phytochemicals encapsulated in nanoparticles on molecular targets in brain tumours, along with their limitations and potential challenges.
Apoptosis or programmed cell death is a carefully synchronized collapse of cells due to protein degradation, fragmentation of DNA. It is an essential part of the life cycle of every multicellular organism including worms to humans. Apoptosis plays a major role in cancer development as well. Various studies confirm the potential of many drugs to change the regulation and ratio of proapoptotic and antiapoptotic factors. Plants are the best-known source of drugs for various kinds of diseases including cancer. Plant secondary metabolites (alkaloids, terpenes and phenolics) are the major constituents used as drugs. Several studies confirm that these secondary metabolites can induce apoptosis by triggering proapoptotic and antiapoptotic factors. In this article, some of the important secondary metabolites and their mode of action as apoptotic triggering agents have been studied.
Cancer is an insidious disease affecting mankind in every country. The progression of cancer cells from one part of the body to another (metastasis) is one of the biggest problems in curing cancer. The present study brings new hope of future therapies to fight cancer. Designing an appropriate food to maintain proper health has become a necessity worldwide. Due to this, the food industries in many countries are modifying their products as a response to consumer demands. In recent years, many of the natural products are gaining popularity as nutraceuticals.
the bioactive LEO phytocomponents are useful for a myriad of medicinal properties including anti-microbial, anticancer, antioxidant, insecticidal, and antimalarial activities (Figure 2). Although LEO and its constituents have shown anticancer activity in vitro, and, in some cases, in animal studies, only a few researchers to date have tested the delivery of its bioactive components combined with nanoparticles or delivery systems. a variety of applications, from food safety and food preservation, in terms of antioxidant potential as well as for antifungal properties, to applications in agriculture and veterinary medicine, and as coatings on biopolymers for surgery (maxillofacial silicone specimens in dentistry, other medical implants) have been recently proposed. The ability of LEO terpenes to stop bacteria and fungi from growing in biofilms has also a wide array of applicative uses in medicine and surgical devices, and in industrial solutions to biocorrosion, biofouling, biodegradation, water microbiology, and the control of bacterial quorum sensing signals [103]. The ability to modify the materials used in medical devices allows the application of LEO components to make such surfaces resistant to biofilm formation.
Herbal oils, also known as oil extracts, are obtained from herbs and plant sources; they possess therapeutic benefits. It is well-known that synergistically a combination of nutrients, bioactive components, antioxidants and biostimulants proved to be more effective. These therapeutic compounds can be obtained from herbs using gentle nondestructive oil extraction techniques. There are different extraction techniques like solvent extraction, hydro-distillation, and steam are used for extracting oils. The composition of herbal oils varies depending upon these extraction techniques. Their chemistry is different from each other and the amount of herbal oil also varies from plant to plant and species to species within the same plant. In this chapter, different herbal oils extracted from various plants (citrus, rosemary, oregano, etc.) and their significant therapeutic benefits are reviewed. According to studies, 30% of herbal oils are being used to treat rheumatoid arthritis and joint diseases where as 10% is being used for arthralgia as antiinflammatory. Moreover, 20% herbal oil is used for the treatment for various skin diseases where as 10% used orally to treat and improve the neuro-functioning as neuro-tonics. Gastrointestinal disorders also treated with the use of herbal oils.
Cancer is a disorder characterized by disordered cell growth due to genetic mutations and environmental factors, which can affect the most varied tissues and organs, as well as spread to distant tissues from the initial focus through the bloodstream and lymphatic vessels. Breast cancer, classified according to the cells involved either intraductal or intralobular, accounts for 20% of all cancers in the world. The treatment of breast cancer encompasses several therapeutic approaches, each of which has its efficacy and particular side effects. Since the number of individuals bearing this disease increases every year and the therapy may fail, the search for new, more effective therapies with fewer side effects is needed. In this sense, mammary tumor cells of the MCF-7 cell line are a model of great importance for studies of potential anticancer drugs. The plant Eremanthus erythropappus (EE), popularly known as Candeia, stands out for the production of essential oil (EO) rich in alpha-bisabolol (α-B), a substance with antitumor properties. Thus, the present study evaluated the in vitro cytotoxic effects of EE EO α-B rich on the MCF-7 cell line since there are no records in the literature of the cytotoxic effects of the refered EO on this lineage. In addition, it is possible that there is a synergy of the other constituents of EO, which may potentiate the antitumor effect of α-B. Our findings allowed us to conclude that the tested cell types (MCF-7 tumor cells and 3T3 fibroblasts) are sensitive to the toxic effects of EE and α-B OE after 24h exposure, and that effect has been shown to be a concentration dependent. However, although the EO of EE has the α-B as the main constituent, its cytotoxicity profile differs in relation to the isolated α-B, being isolated α-B capable of exerting a lower cytotoxic effect on the fibroblasts, a desirable characteristic and that EO of EE did not present. Thus, α-B is the most promising antitumor agent, although in vivo experiments are required to determine its safety and efficacy. With respect to EE, other EO constituents need to be assessed alone or in combination with α-B in order to identify which component (s) are responsible for the high cytotoxicity found for 3T3 fibroblasts.
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.
Bioassay-guided investigation of the ethanol extract of Peperomia galioides using a tensile strength method in mice as a monitor led to the isolation of epi-alpha -bisabolol (1) (ED50 155 mug/mL). An in vivo healing study of selected commercially available monoterpenoids yielded two bioactive compounds, alpha -bisabolol (2) and a-terpineol (3) (ED50 of 228 and 240 mg/g mouse, respectively).
Neuronal death following ischemic insults has been thought to reflect necrosis. However, recent evidence from several labs suggests that programmed cell death, leading to apoptosis, might additionally contribute to this death. We have used both in vitro and in vivo models to study the role of apoptosis in ischemic cell death. Some features of apoptosis (TUNEL staining, internucleosomal DNA fragmentation, sensitivity to cycloheximide) were observed following transient focal ischemia in rats. Brief transient focal ischemia was followed by delayed infarction more than 3 days later; this delayed infarction was sensitive to cycloheximide. A cycloheximide-sensitive component of neuronal cell death was also observed in cultured murine neocortical neurons deprived of oxygen-glucose in the presence of glutamate receptor antagonists. This presumed ischemic apoptosis was attenuated by caspase inhibitors, or by homozygous deletion of the bax gene. Neurons may undergo both apoptosis and necrosis after ischemic insults, and thus it may be therapeutically desirable to block both processes.
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.
By using a potential-dependent J-aggregate-forming delocalized lipophilic cation, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine++ + iodide (JC-1), we find that membrane potentials across mitochondria in a living cell can be heterogeneous. Remarkably, even within a long contiguous mitochondrion, regional heterogeneity in membrane potentials appears to be possible.
Considering the survival time of patients with malignant gliomas indication for chemotherapy in spite of side effects is recommended. One third of them are living 2 years, some even longer. Before starting such a treatment a critical evaluation is mandatory, a prolongation of dying must be avoided. In addition personal human care to the patient and his family has a great importance.
The tetrazolium salt (MTT) method involving conversion of MTT to coloured formazan by cells serving as indirect measurements of cell growth/cell kill has been reported by several groups, although technical problems have been encountered. The present investigation was undertaken in order to delineate what laboratory variables have direct influence on the sensitivity and reproducibility of the method. The pH of the extraction buffer was of the utmost importance, since it was demonstrated that a pH greater than 5 would give rise to false signals. Furthermore, modifying the composition of the extraction buffer, all formazan dye grains were solubilised, totally. A direct comparison with published methods demonstrated that only the modified method would yield 100% higher signals without increasing the background. In contrast to previous reports, it was shown that phenol red does not interfere with the measurements and no washing steps are required since all ingredients can be added subsequently. Serum proteins at concentrations up to 25% have no influence on the result. All samples can be measured in an ELISA scanner at 570 nm with little intra-assay variation.
Several in vitro chemosensitivity assays have been developed for predicting clinical response to chemotherapeutic and biologic agents, alone and in combinations. The most widely accepted assay is the colony forming assay (CFA) which assesses the clonogenic capability of stem cells. Other methods include growth inhibition assays by evaluating cell number; thymidine incorporation; or amino acid uptake. More recently an automatic colorimetric technique utilizing crystal violet dye or a tetrazolium (MTT) vital dye has been developed for more rapid assessment of cytotoxic or growth inhibitory activity in vitro. Several reports have compared the results of in vitro tests with patients' clinical response. Two major problems affect the predictive value of in vitro chemosensitivity tests. The foremost is cellular heterogeneity which exists within a single tumor as well as between tumors. Artificial selective pressure inherent to tissue culture system is the other problem. In general, in vitro tests predict clinical resistance more consistently than clinical sensitivity. However, chemosensitivity assays remain useful in screening new agents and preclinical modeling of clinical trials.
There continues to be an extensive effort to develop chemotherapeutic approaches to the treatment of malignant gliomas of the brain. In the past 5 years there have been literally hundreds of trials of new agents, combinations of old and new agents, and even new routes and approaches to the delivery of chemotherapy.
In this review, the literature has been studied and the individual reports analyzed to evaluate the impact of the new findings on clinical management of the patient with malignant glioma of the brain. The major areas of progress include the addition of new drugs with varying modes of action, the use of combinations of drugs in a synergistic fashion, and the development of new routes of drug delivery. None of the advances has brought about the revolution in clinical care that is so eagerly sought, but clearly the amount of new knowledge gained by these studies helps in understanding how to use chemotherapy more effectively. Furthermore, the remarkable degree of interest and involvement in the use of chemotherapy promises that an even greater number of patients with malignant gliomas will be considered for vigorous and enthusiastic clinical management programs even if chemotherapy itself is not the key modality in the treatment of a specific patient.
Cultured human glioma cells were found to produce soluble factors that can modulate the in vitro proliferative response of purified T lymphocytes stimulated by phytohemagglutinin (PHA). Neoplastic tissue was removed during surgery for brain glial tumors and cultured in vitro. The glial nature of the neoplastic cells was verified by means of anti-glial fibrillary acidic protein immunohistochemical staining. Serum-free supernatants from these cultures proved capable of suppressing in vitro proliferation of PHA-stimulated T lymphocytes. Suppression was reduced when indomethacin or aspirin was added to the culture medium. Thin-layer chromatography revealed the presence of prostaglandins and other arachidonic acid derivatives in the supernatants. The radioimmunoassay used to quantify the prostaglandin E2 (PGE2) in the supernatants showed detectable amounts of PGE2, which disappeared after the cultures had been treated with anti-inflammatory drugs. These data support the hypothesis that tumoral glial cells can play a role in the host immune response in the central nervous system, namely by producing soluble factors.
Clonogenic cell and animal survival studies were used to determine the most effective BCNU therapy schedule in the 9L rat brain-tumor model. Survival of tumor cells following a single LD 10 dose of BCNU (13.3 mg/kg intraperitoneally) was compared to cell survival after one to four daily 0.5 × LD 10 doses. The posttreatment kinetics of surviving clonogenic cells were investigated at various times after BCNU was given in single doses of 0.25 to 1 × LD 10 and in two daily doses of 0.5 × LD 10 . The cell kill was greater, time to reinitiation of cell growth was later, posttreatment rate of clonogenic cell proliferation was slower, and the interval to total repopulation of the clonogenic cell pool was longer with a single LD 10 dose as compared to the multiple-dose schedules. Animal survival studies confirmed that a single LD 10 dose of BCNU was at least as effective as a cumulative level of up to 1½ times that amount when treatment was administered in smaller doses, regardless of the fractionation schedule.
Clinical experience with patients harboring malignant brain tumors has shown that a single BCNU dose of 185 to 200 mg/sq m is tolerated well. Results of these animal experiments suggest that this therapy should have anti-tumor activity at least equivalent to the more commonly employed schedule of 80 mg/sq m/day given for 3 days. Although direct comparison of treatment efficacy using the two schedules is not possible, no adverse clinical effects have been observed with the recently adopted single-dose schedule. Furthermore, the duration of patient hospitalization for chemotherapy has decreased.
The American Cancer Society's Department of Epidemiology and Statistics reports its 30th annual compilation of cancer incidence, survival, and mortality data for the United States and around the world.
In a number of experimental systems, the early stage of the apoptotic process, i.e. the stage which precedes nuclear disintegration, is characterized by the breakdown of the inner mitochondrial transmembrane potential (delta psi m). Here we address the question as to whether mitochondrial permeability transition (PT) pores may account for the delta psi m dissipation in lymphocyte apoptosis. Drugs known for their PT-inhibitory potential (bongkrekic acid, cyclosporin A, and the non-immunosuppressive cyclosporin A analogue N-methyl-Val-4-cyclosporin A) are capable of preventing the apoptotic delta psi m disruption. Moreover, pharmacological modulation of PT-mediated delta psi m dissipation can prevent apoptosis. Thus, while suppressing the delta psi m disruption, bongkrekic acid also inhibits the apoptotic chromatinolysis. In conclusion, these data are compatible with the hypothesis that apoptotic delta psi m disruption is mediated by the formation of PT pores and that PT-mediated delta psi m disruption is a critical event of the apoptotic cascade.
The Surveillance Research Program of the American Cancer Society's Department of Epidemiology and Surveillance reports its 31st annual compilation of cancer incidence, mortality, and survival data for the United States and around the world.
Hospital-based data reported to the National Cancer Data Base (NCDB) were available for over 60,000 patients with a primary brain tumor diagnosed from 1985-1988 and 1990-1992. The most common histologies were glioblastomas, astrocytomas and meningiomas. Five-year survival rates for these tumors were 2%, 30% and 70% respectively. Histology, age at diagnosis, behavior, and location were important variables in estimating survival. Comparisons with population-based registry data suggest that the malignant tumors are well represented in NCDB, but the benign histologies are under-reported. Survival estimates for the malignant tumors are comparable to previously reported studies. The NCDB provides recent information on brain tumor distribution and survival patterns not available in other large databases.
Malignant brain tumors are the most common solid tumors in children. The overall prognosis for this group of patients is still poor, emphasizing the importance of more effective therapies. Betulinic acid (Bet A) has been described as a novel cytotoxic compound active against melanoma and neuroblastoma cells. Here we report that Bet A was active against medulloblastoma and glioblastoma cell lines. In addition, Bet A exerted cytotoxic activity against primary tumor cells cultured from patients in 4 of 4 medulloblastoma-tumor samples tested and in 20 of 24 glioblastoma-tumor samples. Since a small percentage of primary-glioblastoma-tumor cells (4/24) did not respond to Bet-A treatment, resistance to Bet A might occur. Induction of apoptosis by Bet A involved mitochondrial perturbations, since inhibition of the mitochondrial permeability transition by the mitochondrion-specific inhibitor bongkrekic acid (BA) reduced Bet-A-induced apoptosis. In addition, mitochondria undergoing Bet-A-induced permeability transition triggered DNA fragmentation in isolated nuclei. Cytochrome c was released from mitochondria of Bet-A-treated cells, and might be involved in activation of caspases. Following treatment with Bet A, caspase-8, caspase-3 and PARP were proteolytically processed. Inhibition of caspase cleavage by the broad-range caspase inhibitor zVAD.fmk strongly reduced Bet-A-induced apoptosis, indicating that apoptosis was mediated by activation of caspases. Since Bet A did not exhibit cytotoxicity against murine neuronal cells in vitro, these findings suggest that Bet A may be a promising new agent for the treatment of medulloblastoma and glioblastoma cells that clearly warrants further pre-clinical and clinical evaluation.
Studies performed over the past five years have demonstrated that there are two major cell-intrinsic pathways for inducing apoptosis, one that begins with ligation of cell surface death receptors and another that involves mitochondrial release of cytochrome c. Several reports have suggested that anticancer drugs kill susceptible cells by inducing expression of death receptor ligands, especially Fas ligand (FasL). Other reports have indicated that chemotherapeutic agents trigger apoptosis by inducing release of cytochrome c from mitochondria. In this review, we describe the two prototypic death pathways, indicate experimental approaches for distinguishing whether chemotherapeutic agents trigger one pathway or the other, summarize current understanding of the role of the two pathways in chemotherapy-induced apoptosis, and discuss the implications of these studies for mechanisms of resistance to chemotherapeutic agents.
Bioassay-guided investigation of the ethanol extract of Peperomia galioides using a tensile strength method in mice as a monitor led to the isolation of epi-alpha-bisabolol (1) (ED(50) 155 microg/mL). An in vivo healing study of selected commercially available monoterpenoids yielded two bioactive compounds, alpha-bisabolol (2) and alpha-terpineol (3) (ED(50) of 228 and 240 microg/g mouse[corrected], respectively).
Apoptosis is a complex process that removes aging or injured cells from the body and occurs in a wide variety of organisms. Cell death has always been an integral aspect of the study of pathology, but only over the last 30 years or so has the interest in apoptosis gained appreciation in this field. This review analyzes pertinent aspects of apoptosis, from Virchow's initial descriptions of necrobiosis to more modern research, and reviews some of the key events and molecules involved in the process. Finally, the role of apoptosis in certain diseases and its importance in the clinical setting is addressed.
Asiatic acid (AA), a triterpene, decreased viability and induced apoptosis of HepG2 human hepatoma cells in a dose-dependent manner. AA also markedly increased intracellular Ca(2+) level, which was blocked by TMB-8 and dantrolene, intracellular Ca(2+) release blockers, but not by EGTA, an extracellular Ca(2+) chelator. Moreover, AA-induced apoptosis was significantly suppressed by treatment with TMB-8 and dantrolene, suggesting that intracellular Ca(2+) release may play an essential role in the AA-induced apoptosis. In addition, AA profoundly increased protein level of p53, which was also inhibited by BAPTA/AM, an intracellular Ca(2+) chelator, TMB-8 and dantrolene. Treatment with A23187, a Ca(2+) ionophore, or thapsigargin, a Ca(2+)-ATPase inhibitor, alone enhanced p53 nuclear accumulation, indicating that p53 accumulation is dependent on intracellular Ca(2+) increase. Furthermore, the viability of Hep3B, p53-null cells, was much higher than that of HepG2, p53-wild type cells, when treated with AA. Taken together, these results suggest that AA induced apoptosis through increased intracellular Ca(2+), which, in turn, enhanced p53 expression in HepG2 cells. These results further suggest that AA may be a valuable agent for the therapeutic intervention of human hepatomas.
Different preparations of chamomile (Matricaria chamomilla) are used to treat various diseases, including inflammation and cancer; however, no studies on the plant's antigenotoxic capacity have been made. The aim of the present work was to determine the inhibitory effect of the chamomile essential oil (CO), on the sister chromatid exchanges (SCEs) produced by daunorubicin and methyl methanesulfonate (MMS) in mouse bone marrow cells. CO was analyzed and was found to contain 13 compounds, mainly bisabolol and its oxides, chamazulene, farnesene, germacrene and other sesquiterpenes. Initially, a toxic and a genotoxic analysis of CO were made; both showed negative results. To determine whether CO can inhibit the mutagenic effects induced by daunorubicin, one group of mice was administered corn oil, another group was treated with the mutagen (10 mg/kg), a third group was treated with 500 mg/kg of CO; three other groups were treated first with CO (5, 50 and 500 mg/kg) and then with 10 mg/kg of daunorubicin. In the case of MMS, the experimental groups consisted of the following: the negative control group which was administered corn oil, a group treated with 25 mg/kg of MMS, a group treated with 1000 mg/kg of CO, and three groups treated first with CO (250, 500 and 1000 mg/kg) and then with MMS (25 mg/kg). The results indicated a dose-dependent inhibitory effect on the SCEs formed by both mutagens. In the case of daunorubicin, a statistically significant result was observed in the three tested doses: from the lowest to the highest dose, the inhibitory values corresponded to 25.7, 63.1 and 75.5%. No alterations were found with respect to the cellular proliferation kinetics, but a reduction in the mitotic index was detected. As regards MMS, the inhibitory values were 24.8, 45.8 and 60.6%; no alterations were found in either the cellular proliferation kinetics or in the mitotic indices. Our results suggest that CO may be an effective antimutagen that could be considered for further study.
Improved treatment of a brain-tumor model
- Rosenblum
Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis
- Zamzami