Antineoplastic agents 338. The cancer cell growth inhibitory. Constituents of Terminalia arjuna (Combretaceae)

ArticleinJournal of Ethnopharmacology 53(2):57-63 · September 1996with 57 Reads
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Abstract
By means of bioassay-guided separation methods, the cancer cell growth inhibitory constituents residing in the bark, stem and leaves of the Mauritius medicinal plant Terminalia arjuna (Combretaceae) were examined. The cancer cell line active components were found to be gallic acid, ethyl gallate, and the flavone luteolin. Only gallic acid was previously known to occur in this plant. Luteolin has a well established record of inhibiting various cancer cell lines and may account for most of the rationale underlying the use of T. arjuna in traditional cancer treatments. Luteolin was also found to exhibit specific activity against the pathogenic bacterium Neisseria gonorrhoeae.

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    Background: Medicinal plants have been a major source of therapeutic agents from ancient times to cure diseases. The evaluation of rich heritage of traditional medicine is essential. The bark of Terminalia arjuna is rich in polyphenols (60–70%) including flavonoids and tannins. Aim: The aim of the present investigation is to highlight the anticarcinogenic and antimutagenic potential of extracts of T. arjuna. Subject and methods: In this experiment we have used human lymphocyte culture and bone marrow cells of albino mice as assay system. The parameters studied included chromosomal aberrations (CA), sister chromatid exchanges (SCEs) and cell growth kinetics (RI) both in the presence and in the absence of exogenous metabolic activation system for in vitro experiment, whereas total aberrant cells and the total frequencies of aberrations were taken for in vivo study. Results: The role of T. arjuna extracts in reducing metaphase aberrations due to aflatoxin B1 is quite significant, the reduction varying from 23.49%, 42.47%, and 59.65% down to 12.32%, 28.00%, and 36.88% respectively at the highest dose (TA4) for the three different durations viz., 24, 48 and 72 h. Similarly the number of sister chromatid exchanges got reduced from a higher level of 15.00 ± 1.40 per cell to 7.70 ± 0.50 per cell with S9 mix at 48 h of treatment. The replication index was enhanced from 1.33 to 1.55 in vitro. Similar trends were noticed in the in vivo experiments i.e., effective reductions in clastogeny ranging from 15.22% to 54.82% from the mutagen treated positive control and the total frequencies in aberrant cells got reduced from 429 due to AFB1 to 141 due to 5th concentration of Terminalia extracts at 32 h of exposure. Conclusion: The ameliorating potential of Terminalia extracts was dose and time dependant.
  • Book
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    Cancer is a class of diseases characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct invasion into adjacent tissue or by implantation into distant sites (metastasis) (Mokhtar,1998). There are multiple causative and risk factors responsible for developing the disease, these causal factors may act together or in a sequence to initiate or promote carcinogenesis (ACS,2005). The cause or causes of many cancers remain unknown; the study of Surh, (1999) revealed that 80% to 90% of all cancers are caused by environmental risk factors. (AICR, 2007). Cancer is classified as the second leading cause of death after cardiovascular disease in Europe and in United States (Heron et al. ,2009). Many cancers have the capacity to kill the patient with more than 3 million new cases and 1.7 million deaths each year (Ferlay et al., 2007). Chemotherapy is one of the conventional cancer treatments in addition to surgery and radiotherapy. All these types of treatments are costly and carry a high risk of side effects (Devita et al., 1997). The other problem encountered with such drugs and radiation therapy is that they are toxic to normal dividing cells as well as to cancer cells (Allen, 2002).Although major advances have been made in the chemotherapeutic treatments of cancers, particularly in hematological malignancies, part of patients either do not respond to anticancer therapy or relapse after the initial response or ultimately dies from their metastasis. Thus, continues efforts for discovering new anticancer therapeutic agents remain critically important (Grever et al., 1996). Yang and Baltimore, (2005) developed a more recent method of therapy called "instructive immunotherapy" which combines stem cell therapy, gene therapy and immunotherapy to guide the host to develop in vivo, a large population of antigen-specific T cells. Davis et al., (1999) showed a reduction in adverse effects of chemotherapy and radiation when given concurrently with antioxidants. The efforts focused on complementary alternative medicine which can be useful to enhance a person's response to treatment and provide relief from symptoms without interfering with the effectiveness of standard cancer therapy (Brown et al., 2003). Herbal medicine has a vital role in the prevention and treatment of cancer. Actually, more than 50% of drugs used during the last 20 years are directly or chemically altered natural products (Newman et al., 2003). The increased use of herbal medicines in developed countries is mainly due to the failure of modern medicine in providing effective treatment for chronic diseases and emergence of multi-drug resistant bacteria and parasites (W.H.O., 2002). According to a report of world health organization (W.H.O.), 70% of the world population uses medicinal plants to cure diseases through their traditional practitioners. A great deal of pharmaceutical research in advanced countries had considerably improved quality of the herbal medicines used in treatment of cancer. With advanced knowledge of molecular science, purifications, isolations and structure elucidation techniques, helped to identify various anticancer herbs and developed remedies that may cure cancers. Many efforts have begun during the last years in Iraq and Iraqi Center for Cancer and Medical Genetics Research (ICCMGR), to evaluate the cytotoxic effects of medicinal herbs as alternative safe source of treatment. Different pattern of inhibition on tumor cell growth by green and black tea extracts was demonstrated by Sa'eed (2004). Ibrahim (2005) demonstrated that Saliva triloba extracts have a direct cytotoxic effect on different malignant cell lines. Al-Dabhawi (2005) found that Artemisia herba alba extracts have a potent cytotoxic activity against tumor cell lines in a concentration- and time-dependent manners. Cyperus rotundus (Al-Hilli , 2004), and Nerium oleander (Abdul-Jalill, 2006) have shown significant cytotoxic effects against malignant cell lines in vitro. Ubead (2006) evaluate the anticancer effects of the cold aqueous , hot aqueous and ethanolic extract of the Olea europea (Al-Zaitoon or Olive) on cancer cell lines as in vitro and in vivo. ). Aqueous and methanolic root extract of C. spinosa, possess considerable inhibition of Mammary Adenocarcinoma 3(AMN3) cells , whereas Hep-2 tumor cell line is sensitive to aqueous root extract as well as aqueous leave extract. Aqueous and methanolic root extract of C. spinosa has ability to reduce the tumor volume in vivo( Al- Asady, 2007) . Aqueous root extract of Echium sericeum posses inhibitory effect on the growth of normal kidney cell line (Vero),human larynx carcinoma( Hep-2) and Rhabdomyosarcoma ( RD) cell lines (Al-Habbib and Al-Asady, 2009). Hade,(2009) investigate the effect of the aqueous and crude alkaloids extracted from the leaves of Convolvulus arvensis on two malignant cell lines Hela and RD. Al- Naimy ,(2011) evaluate the cytotoxic effect of apricot seed (Prunus armeniaca) of methanolic extract on different tumor cell line . Polyphenol mature fruit extract has cytotoxic effects on Hela and hep-2 tumor cell line (Al-Asady et al.,2012a). Al- Barzanjy (2012) showed the methanolic and aqueous extracts of Salvia officinalis and Pistasia khinjuk extracts has high cytotoxic activity on two tumor cell lines RD and AMN3. Alol et al. ,(2012) Showed the high cytotoxic effect of apigenin extracted from Petroselinum sativum seeds on mammary adenocarcinoma (AMN3).
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    Objective: To evaluate the α-amylase inhibitory potential of nine herbal plants in regulating postprandial hyperglycemia. Materials and Methods: In vitro α-amylase inhibition assay using starch-iodine was performed. α-amylase inhibition delays breakdown of starch and prevents glucose release to reduce postprandial hyperglycemia. Results: The plants screened were Artocarpus altilis, Aconitum heterophyllum, Acorus calamus, Berberis aristata, Cassia auriculata, Cyprus rotundus, Mesua ferrea, Plumbago zeylanicum and Terminalia arjuna. Positive control Acarbose showed IC 50 at 14.24 µg/ml. Methanolic extract of C. auriculata (flower), T. arjuna (bark) and P. zeylanicum (rhizome) exhibited the best inhibitory activity with IC 50 value of 37.28 µg/ml, 48.75 µg/ml and 68.66 µg/ml, respectively. Conclusion: From the present study, we conclude that C. auriculata flower had displayed maximum inhibition against α-amylase.
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    This review paper focused on ethno-pharmacological uses and phytochemical constituents of Terminalia arjuna Roxb., an important medicinal plant of Bangladesh, used in various indigenous system of medicine. This review has been conducted to pile up information that is available in different scientific literatures. It is observed that a large number of phytochemical components have been obtained from the plant e.g. arjunin, arjunetin, gallic acid, terminic acid, pyrocatechols, luteolin, β-sitosterol, calcium, magnesium, zinc, copper and these components exhibit various medicinal and pharmacological activities such as anti-mutagenic, anti-bacterial, anti-viral, anti-oxidant, anti-inflammatory, antiatherosclerotic, anti-diabetic etc. The present comprehensive update review is therefore, an effort to give detailed information on phytochemical and pharmacological studies of T. arjuna Roxb. and this information will help the researchers to carry out research on this pharmaceutically important medicinal plant.
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    Herbal drug products have special place in the pharmaceutical world. Terminalia chebula is been used in various traditional medicines for treatment of various diseases. The objective of the current research work was to study the anti-HIV I activity of the crude extract of Terminalia chebula and its chemical constituent gallic acid. Terminalia chebula fruit extract and gallic acid showed the IC50 was of 84.81 μg/ml and 71.99 μM respectively for the HIV integrase strand transfer inhibition activity. The crude extract of Terminalia chebula and gallic acid showed dose dependent inhibition on different HIV-1 strains such asNARI-VB 28, NARI-29, NARI-VB 30, NARI-VB 39, NARI-VB 49 and HIV-1 92 HT599. The Terminalia chebula fruit extract and gallic acid did not show the cytotoxicity against the MT2 cells at the concentration used in the study. Terminalia chebula fruit extract and its constituents can be further exploited for future plant based anti-HIV.
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    Background Anisochilus carnosus (L.f.) wall (Lamiaceae), an annual herb which grows at high altitude is used extensively in folk medicine for the treatment of ailments such as gastric ulcer and skin diseases. The aim of our study was to evaluate the anticancer activity of different extracts of the leaves of A.carnosus. An attempt was also made to estimate the luteolin content in different extracts of Anisochilus carnosus by HPLC (High Performance Liquid Chromatography). Methods In the current study, we explored the cytotoxic potential of petroleum ether, ethanolic and aqueous extracts of A.carnosus against breast adenocarcinoma cell line (BT-549), by in vitro MTT and SRB assay. We also detected the luteolin content in different extracts (ethanolic and aqueous) of A.carnosus by using HPLC as a tool of analysis. Results The results demonstrate that petroleum ether and ethanolic extract of A.carnosus showed potent cytotoxic effect against BT-549 with an IC50 of 22.5 μg/ml (petroleum ether extract) and 87.24 μg/ml (ethanolic extract), by SRB assay, and 18.35 μg/ml (petroleum ether extract) and 58.64 μg/ml (ethanolic extract), by MTT assay. The aqueous extracts showed less cytotoxic effect with an IC50 of 211.26 μg/ml (by SRB assay) and 238.91 μg/ml (by MTT assay). HPLC results of luteolin content in various extracts using luteolin as the marker compound indicated the ethanol extract to contain the highest concentration of luteolin (0.372% w/w). The aqueous extract contained lower concentration of luteolin (0.282% w/w). Conclusion Our findings demonstrate that petroleum ether and ethanolic extract of A.carnosus shows promising anticancer activity and has the potential to be developed into a therapeutic option for the treatment of cancer.
  • Article
    Physicochemical studies on small molecules interactions with different polymorphs of DNA are relevant for elucidation at the molecular level of the processes occurring in vivo. In our work, various spectroscopic techniques combined with molecular modeling computations have been used to explore the interactions of Luteolin (LTN), a pharmacologically important bioactive flavone, with two polymorphic forms of natural DNA. These include the low pH induced left-handed protonated and right-handed B form of DNA in aqueous buffer medium. The association was characterized by hypochromic and red shifted absorption maxima, enhancement in fluorescence intensity and strong perturbation in the circular dichroic (CD) spectra. Binding parameters along with significant thermal stabilization indicate greater extent of association of LTN to the protonated form in compared to the native B form structure of DNA. Viscometric and molecular docking studies together infer the binding mode of LTN to the protonated DNA is external stacking while with B DNA it is intercalation.
  • Article
    Metastatic lung cancer is a leading cause of mortality and has a mortality rate of ≥90%. Isolinderalactone (ILL) is a sesquiterpene lactone compound that has been used in traditional Chinese medicine. Research has demonstrated that ILL has anti-inflammatory and anti-proliferative properties; however, to the best of our knowledge, studies investigating whether ILL can inhibit lung cancer cell metastasis have not been conducted. In the present study, 1-10 µM ILL was applied in the culturing of the A549 lung cancer cell line to investigate the effects of ILL on the invasion and migration of lung cancer cells, including whether the possible mechanisms of ILL are associated with the expression of matrix metalloproteinase (MMP)-2 and NME/NM23 nucleoside diphosphate kinase 1 (NM23-H1) genes. The results of the present study indicated that ILL inhibited the invasion and migration of the A549 cancer cells and exhibited a dose-response association. ILL also significantly inhibited the protein expression and activity of MMP-2 (P<0.05), exhibiting a trend similar to that of its invasion- and migration-associated properties. Further research revealed that ILL significantly increased the expression of NM23-H1 protein and inhibited the expression of β-catenin protein (P<0.05). The results of the present study is, to the best of our knowledge, the first to confirm that ILL can inhibit the invasion and migration of A549 cancer cells, with the possible mechanisms potentially involving the inhibition of MMP-2 and β-catenin protein expression resulting from the up regulation of NM23-H1 expression.
  • Cardiovascular diseases are the most common cause of deaths worldwide and will become even more prevalent with the recent changes in life style, food habits and environmental pollution. Herbal medicines have been used for cardiovascular diseases and some of their derivatives have become mainstay of human pharmacotherapy. Various clinical and pharmacological studies have indicated the cardioprotective role of Terminalia arjuna in cardiac ailments. The present review is an effort to give a detailed survey of the literature summarizing the experimental studies of T. arjuna on cardiovascular system. It mainly focuses on experimental studies pertaining to various aspects of cardiovascular functions, autonomic control of myocardial functions, molecular mechanisms of its action and Cardiac histopathology. © 2018, Association of Physiologists and Pharmacologists of India. All rights reserved.
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  • Article
    Medicinal plants have been a main source of therapeutic agents from ancient time to cure diseases. Terminalia arjuna (Roxb.) Wight & Arn. (T. arjuna) is one of the most accepted and beneficial medicinal plants in indigenous system of medicine for the treatment of various critical diseases. This comprehensive review provides various aspects of its ethnomedical, phytochemical, pharmacognostical, pharmacological and clinical significance to different diseases particularly in cardiovascular conditions. This plant has a good safety outline when used in combination with other conventional drugs. This review highlights various medicinal properties of T. arjuna through different studies such as antioxidant, hypotensive, anti-atherogenic, anti-inflammatory, anti-carcinogenic, anti-mutagenic and gastro-productive effect.
  • Article
    Chemoprevention is regarded as one of the most promising and realistic approaches in the prevention of human cancer. Ellagic acid (EA) has been known for its chemopreventive activity against various cancers and numerous investigations have shown its apoptotic activity both in vivo and in vitro. The present study was focused to elucidate the anticancerous effect and the mode of action of EA against HCT-15 colon adenocarcinoma cells. Cell viability was assessed using trypan blue assay at different concentrations. EA also promoted cell cycle arrest substantially at G2/M phase in HCT-15 cells. The activities of alkaline phosphatase and lactate dehydrogenase were decreased upon EA treatment, which shows the antiproliferative and the cytotoxic effects, respectively. The production of reactive oxygen intermediates, which were examined by 2,7-dichlorodihydrofluorescein diacetate (H2DCF-DA), increased with time, after treatment with EA. In further studies, EA inhibited proliferation-associated markers proliferating cell nuclear antigen and cyclin D1. The induction of apoptosis was accompanied by a strong inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway by EA. The expression of PI3K and pAkt was down-regulated in EA-treated cells, compared to normal cells. Further, EA promoted the expression of Bax, caspase-3, and cytochrome c, and suppression of Bcl-2 activity in HCT-15 cells that was determined by western blot analysis. Increased annexin V apoptotic cells and DNA fragmentation also accompanied EA-induced apoptosis. In conclusion, EA increased the production of ROS, decreased cell proliferation, and induced apoptosis in HCT-15 cells, and thus can be used as an agent against colon cancer.
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    A highly sensitive and specific HPLC-ESI-LTQ-Orbitrap combined with a multiple mass defect filter (MMDF) method was used to profile and identify the metabolites of 11,13α-dihydroixerin Z (DIZ) in rats. Plasma was collected after intravenous administration of DIZ to the rats (50 mg kg−1). Based on the accurate mass measurements, the retention time and mass fragmentation patterns, in total, 40 metabolites were tentatively identified and characterized. The distribution of the metabolites in rats was reported for the first time. Hydroxylation, hydrolysis, methylation, cysteine conjugation, glutathione (GSH) conjugation, sulfate conjugation, N-acetylcysteine conjugation, and glucuronidation were found to comprise the major metabolic reactions of DIZ in rats. These results are very helpful for the better comprehension of the metabolism and can also give strong indications about the effective forms of DIZ in vivo.
  • Article
    Flavonoids are bioactive compounds found in foods such as tea, chocolate, red wine, fruit, and vegetables. Higher intakes of specific flavonoids and flavonoid-rich foods have been linked to reduced mortality from specific vascular diseases and cancers. However, the importance of flavonoids in preventing all-cause mortality remains uncertain. The objective was to explore the association between flavonoid intake and risk of 5-y mortality from all causes by using 2 comprehensive food composition databases to assess flavonoid intake. The study population included 1063 randomly selected women aged >75 y. All-cause, cancer, and cardiovascular mortalities were assessed over 5 y of follow-up through the Western Australia Data Linkage System. Two estimates of flavonoid intake (total flavonoidUSDA and total flavonoidPE) were determined by using food composition data from the USDA and the Phenol-Explorer (PE) databases. During the 5-y follow-up period, 129 (12%) deaths were documented. Participants with high total flavonoid intake were at lower risk [multivariate-adjusted HR (95% CI)] of 5-y all-cause mortality than those with low levels of total flavonoid consumption [total flavonoidUSDA: 0.37 (0.22, 0.58); total flavonoidPE: 0.36 (0.22, 0.60)]. Similar beneficial relationships were observed for both cardiovascular disease mortality [total flavonoidUSDA: 0.34 (0.17, 0.69); flavonoidPE: 0.32 (0.16, 0.61)] and cancer mortality [total flavonoidUSDA: 0.25 (0.10, 0.62); flavonoidPE: 0.26 (0.11, 0.62)]. Using the most comprehensive flavonoid databases, we provide evidence that high consumption of flavonoids is associated with reduced risk of mortality in older women. The benefits of flavonoids may extend to the etiology of cancer and cardiovascular disease. © 2015 American Society for Nutrition.
  • Article
    Terminalia arjuna (Roxb) Wight & Arn is a medicinally important tree species of the family Combretaceae. It is used in Indian medicine system due to its high potential for several ailments. Various parts of T. arjuna have been investigated for the presence of phyto-constituents and pharmacological activities. Triterpenoids are mainly responsible for cardiovascular properties while flavonoids, tannins, terpenoids and glycosides are responsible for its anti-oxidant, anti-diabetic, anti-fungal, anti-microbial, anti-mutagenic, anti-diarrhoeal, anti-leishmanial, hypotensive, hypolipidemic, gastroprotective and hepatoprotective properties. Several important phytoconstituents have been isolated from different extracts of T. arjuna. The review aims to compile and analyse the information on phytochemical and pharmacological activities of T. arjuna.
  • Article
    A greenhouse experiment was conducted to determine the effects of medium components and shade treatment on the growth, contents of total phenolics and flavonoids, and 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activity of Youngia sonchifolia. Substrates combined with coco peat and perlite (ratio 70:30 or 50:50, v/v) showed higher plant length, leaf area, and fresh weight than single substrate (P dry wt.] and total flavonoids [mg naringin equivalents kg^{-1} dry wt.] in shoot parts of Y. sonchifoli, showing 110.2 to 119.2 and 128.3 to 146.7 mg kg^{-1}, respectively. The antioxidant potential of the methanol extracts from the plants dose-dependently increased DPPH free radical scavenging activity, and the activity was higher in shoots (50.2 to 80.8%) than in roots (47.7 to 49.8%), and in shading treatment than in no shade.
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    para‑Phenylenediamine (p‑PD) is a potential carcinogen, and widely used in marketed hair dye formulations. In the present study, the role of the protein tyrosine kinase (PTK)/Ras/Raf/c‑Jun N‑terminal kinase (JNK) and phosphoinositide 3‑kinase (PI3k)/protein kinase B (Akt) pathways on the growth of NRK‑52E cells was investigated. The results demonstrated that p‑PD reduced cell viability in a dose‑dependent manner. The cell death due to apoptosis was confirmed by cell cycle analysis and an Annexin‑V‑fluorescein isothiocyanate binding assay. Subsequent to staining with 2',7'‑dichlorofluorescin diacetate, the treated cells demonstrated a significant increase in reactive oxygen species (ROS) generation compared with the controls. The effects of p‑PD on the signalling pathways were analysed by western blotting. p‑PD‑treated cells exhibited an upregulated phospho‑stress‑activated protein kinase/JNK protein expression level and downregulated Ras and Raf protein expression levels; however, Akt, Bcl‑2, Bcl‑XL and Bad protein expression levels were not significantly altered compared with the control. In conclusion, p‑PD induced apoptosis by a PTK/Ras/Raf/JNK‑dependent pathway and was independent of the PI3K/Akt pathway in NRK‑52E cells.
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    A simple and rapid method for simultaneous determination of ten polyphenols in Kudiezi injection has been developed and validated using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) in multiple reaction monitoring (MRM) mode. The chromatographic separation was performed on an ACQUITY UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with a gradient of acetonitrile and 0.5% formic acid (v/v). Ten polyphenols were rapidly analyzed within 10 minutes. Very low limits of detection (LODs) of 0.002–0.630 μg L−1 and limits of quantitation (LOQs) of 0.005–2.930 μg L−1 of the ten components were achieved. The linear calibration range extended from 2.73 to 660.40 μg L−1. The developed method was validated in terms of good linearity (R2 > 0.9990), precision (less than 3.71%) and accuracy (from 97.35 to 102.02%) for ten components. The developed UPLC-ESI-MS/MS method was simple and useful for rapid determination of the constituents in Kudiezi injection.
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    A culture of P388 murine lymphoblastoid cells has been shown to contain type C oncornavirus-like particles budding at the plasma membrane. Occasionally intracytoplasmic type A and immature type B particles were also observed by electron microscope techniques. The discovery of oncornavirus-like particles in the P388 cell line increases the utility of this neoplastic system for detecting potential antineoplastic agents.
  • Studies in Organic Chemistry 39. Carbon-13. NMR of Flavonoids
    • P K Agrawal
    Agrawal, P.K. (1989) Studies in Organic Chemistry 39. Carbon-13. NMR of Flavonoids, Elsevier Science Publishing Com-pany, Inc., New York, NY.
  • Approved standard M2-A4. Performance standards for an-timicrobic disk susceptibility tests. National Committee for Clinical Laboratory Standards Antineoplas-tic agents 31. Oenothera caespitosa
    • Pa Villanova
    • G R Pettit
    • P M Traxler
    • C P Pasc
    National Committee for Clinical Laboratory Standards, 1990. Approved standard M2-A4. Performance standards for an-timicrobic disk susceptibility tests. National Committee for Clinical Laboratory Standards, Villanova, Pa. Pettit, G.R., Traxler, P.M. and Pasc, C.P. (1973) Antineoplas-tic agents 31. Oenothera caespitosa. Lloydia 36, 202-203.
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    A range of 16 derivatives of flavone-8-acetic acid (FAA) with a 6-methyl substituent have been prepared and their anti-tumour activity evaluted in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. While many of the compounds show activity comparable to FAA in vitro, this essentially disappears in vivo, possibly due to degradation before the compounds can reach the tumour site.
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    The trihydroxylated triterpene acids arjunolic acid and asiatic acid were found in ether extracts of the woods of Terminalia brassii and of T. complanata. Asiatic acid has not previously been reported as a constituent of the genus Terminalia. A similar extract of T. impediens yielded the tetrahydroxy acid terminolic acid as the major constituent; this acid was also detected as a minor constituent of T. complanata. Terminolic acid, however, does not occur in glycosidic combination in Centella asiatica, as has been recently reported.
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    Blätter von Rhus coriaria mit einem Gehalt von 23.35 % an Tanninen wurden fraktioniert mit Aethylacetat, Methanol und Wasser extrahiert. Nach Säurehydrolyse des Aethylacetat– und Methanolextraktes wurden die Flavonole Myricetin, Quercetin und Kaempferol zusammen mit Gallussäure, m–Digallussäure, Methylgallat und Ellagsäure papierchromatographisch nachgewiesen. Die Identifizerung aller dieser phenolischen Komponenten wurde durch Ultraviolett–Spektrophotometrie zusätzlich abgesichert. Die Untersuchung der Gerbwirkung zeigte, daß das Blattmaterial von Rhus coriaria das von Mangifera indica weit übertrifft.
  • Article
    Spectral, acid-base, and redox properties of the phenoxyl radicals derived from 3,4-dihydroxybenzene derivatives and selected flavonoids were studied by pulse radiolysis of aqueous solutions. From the pH-dependent changes in the phenoxyl spectra, the dissociation constants were derived. The pK(a), values for the deprotonation of the 3'-OH group in the catechin (pK(a) = 4.6) and rutin (pK(a) = 4.3) radicals are similar to the pK(a) value of the 3,4-dihydroxybenzoate radicals, pK(a) = 4.2, which is expected from their similar electronic structures. Deprotonation of 5- and 7-OH in the catechin and rutin and of 5-OH in the hesperidin radicals has no effect on the radical spectra, which is explained by the inefficient coupling of the A-ring of the flavonoid radicals with the unpaired electron. Because of favorable reduction potentials of the phenoxyl radicals, E(7) = 0.56-0.7 V vs NHE, flavonoids may act as efficient antioxidants of alkylperoxyl and superoxide/hydroperoxyl radicals. The ac kinetic conductivity method was developed for the measurements of the low reaction rate constants of the superoxide radical reactions with flavonoids and phenols in aqueous solutions at pH 10. The rates of the superoxide radical reactions with flavonoids, k = 3 X 10(2)-5.1 X 10(4) M(-1) s(-1), depend on the redox properties and the charge of the flavonoids. The highest rates are measured for the oxidation of quercetin and rutin, whereas the lowest are those for the B-ring monosubstituted derivatives, with substantially higher redox potentials. Uncharged catechin at pH 7 reacts at k = 6.6 X 10(4) M(-1) s(-1), whereas the rate at pH 10, where catechin is doubly negatively charged, is approximately 4 times lower, k = 1.8 x 10(4) M(-1) s(-1). The activation parameters of the oxidation of rutin and trolox at pH 10 and methyl gallate at pH 7 were determined in an attempt to understand why the rates of the superoxide reactions are low despite high driving forces of Delta E greater than or equal to 0.4 V. Low activation enthalpies, Delta H-double dagger = 2.3-3.6 kcal/mol, and negative activation entropies, Delta S-double dagger = -25-28 cal/(mol K), point to an inner-sphere electron-transfer mechanism.
  • Article
    The mutagenicities of 61 flavonoids (naturally occurring flavonoid aglycones and flavonal glycosides and synthetic flavonoids) and those of 11 compounds structurally related to flavonoids were tested with Salmonella typhimurium strains TA100 and TA98. Among the 22 flavone derivatives tested, only wogonin was strongly mutagenic, while five derivatives, apigenin triacetate, acacetin, chrysoeriol, pedalitin, and pedalitin tetraacetate, were only weakly mutagenic. Two bisflavonyl derivatives, neither of which has a 3-hydroxyl group, were not mutagenic. Of the 16 flavonol derivatives tested, all except 3-hydroxyflavone and the tetra- and penta-methyl ethers of quercetin were mutagenic. Of the five flavanone derivatives tested, only 7,4-dihydroxyflavanone was mutagenic, showing weak activity. Of the four flavanonol derivatives tested, hydrorobinetin and taxifolin were weakly mutagenic. Of the six isoflavone derivatives tested, tectorigenin was weakly mutagenic. Of the 11 compounds in the miscellaneous group structurally related to flavonoids, only iso-liquiritigenin was mutagenic, showing weak activity. For the emergence of strong mutagenicity, the double bond between positions 2 and 3 and the hydroxyl group at position 3 are required, except in wogonin, which does not have a hydroxyl group at position 3 but is strongly mutagenic to TA100. The 3-O-acetyl ester of flavonol, quercetin, was mutagenic with S9 mix, but 3-O-methyl ethers were not. Six flavonol glycosides, three quercetin glycosides and three kaempferol glycosides were mutagenic after preincubation with “hesperidinase,” a crude extract of Aspergillus niger. Of 66 flavonoid agylcones and compounds structurally related to flavonoids, quercetin was the strongest mutagen. The carcinogenicity of this compound should be clarified because it is ubiquitously found in vegetables.
  • Article
    The activity-guided fractionation of some medicinal plants led to yield five kinds of natural stilbene compounds namely 3,5-dihydroxy-4′-methoxystillbene(I), rhapontigenin(II), resveratrol (III), rhaponticin(IV) and piceid(V) and two common flavonoids, apigenin(VI) and luteolin(VII) as active principles of the antitumor property, in vitro, against five kinds of human tumor cell lines, A-549, SK-OV-3, SK-MEL-2, XF-498 and HCT15.
  • Article
    The characteristics pattern of differential cytotoxicity of a crude extract of the tropical plant Polymnia fruticosa was found to be similar to those of known tubulin-interactive compounds. Fractionation of the extract led to centraureidin as the major cytotoxic principle. Centaureidin inhibited tubulin polymerization, inhibited the binding of [3H]-colchicine to tubulin, and induced mitotic figure formation in whole cells at cytotoxic concentrations. This is the first known example of a flavone with antimitotic activity.
  • Article
    The content of the potentially anticarcinogenic flavonoids quercetin, kaempferol, myricetin, apigenin, and luteolin of 28 vegetables and 9 fruits was determined by RP-HPLC with UV detection. Fresh foods were purchased in a supermarket, agrocery, and a street market and combined to composites. Processed foods were purchased additionally. Sampling was carried out in spring, summer, winter, and spring of the following year. Quercetin levels in the edible parts of most vegetables were generally below 10 mg/kg except for onions (284-486 mg/kg), kale (110 mg/kg), broccoli (30 mg/kg), French beans (32-45 mg/kg), and slicing beans (28-30 mg/kg). Kaempferol could only be detected in kale (211 mg/kg), endive (15-91 mg/kg), leek (11-56 mg/kg), and turnip tops (31-64 mg/kg). In most fruits the quercetin content averaged 15 mg/kg, except for different apple varieties in which 21-72 mg/kg was found. The content of myricetin, luteolin, and apigenin was below the limit of detection (
  • Tetrahydroxy-3-methoxyflavone, a potent antitumor promoter isolated from Gnaphalium indicum
    • Y Asaka
    • A Ohsaki
    • T Kubota
    • Y Matsukawa
    • Y Satomi
    • H Nishino
    Asaka, Y., Ohsaki, A., Kubota, T., Matsukawa, Y., Satomi, Y. and Nishino, H. (1992) 5,7,3',4'-Tetrahydroxy-3-methoxyflavone, a potent antitumor promoter isolated from Gnaphalium indicum. Kyoto-furitsu [ka Daigaku Zasshi 101,353-359.
  • Article
    Seven compounds, which included some naturally occurring dietary substances, were tested for their inhibitory effects on growth and metabolism of human leukemic CEM-C1 and CEM-C7 cell lines. Among the active compounds the naturally occurring dietary constituents were found to be the most active. The strongest inhibitory effects were observed with 3',4',5,7-tetrahydroxy-flavone (luteolin) and 4,4'-dihydroxychalcone. 31P-NMR spectra of cells incubated for 24 h with 30 microM of either of these compounds show complete ATP depletion. Also glucose uptake by the cells as measured by 13C-NMR is completely inhibited by these compounds. These results may be relevant to the tumor suppressing activity of bioflavonoids and the role of these compounds in chemoprevention.
  • Article
    In vitro studies showed that several flavonoids, tannic acid, gallic acid and fat-soluble vitamins inhibited HeLa and Raji lymphoma cell growth. The inhibition trend exhibited by these compounds was similar for both cell lines, and their growth was inhibited dose dependently. Butein, (10 microM), the most potent anti-proliferative agent, exerted 30% growth inhibition and was more effective on HeLa cells. Retinol (100 microM) inhibited cell proliferation completely. Tannic acid was twice as potent as its monomer gallic acid. From structure-activity consideration, the C2,3-double bond of the flavonoid molecule was important for activity. Flavonoid aglycones were more effective than their corresponding glycosides in suppressing cell growth.
  • Article
    Combretastatin A-4 (CS-A4), 3,4,5-trimethoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, and combretastatin A-2 (CS-A2), 3,4-(methylenedioxy)-5-methoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, are structurally simple natural products isolated from the South African tree Combretum caffrum. They inhibit mitosis and microtubule assembly and are competitive inhibitors of the binding of colchicine to tubulin [Lin et al. (1988) Mol. Pharmacol. 34, 200-208]. In contrast to colchicine, drug effects on tubulin were not enhanced by preincubating CS-A4 or CS-A2 with the protein. The mechanism of their binding to tubulin was examined indirectly by evaluating their effects on the binding of radiolabeled colchicine to the protein. These studies demonstrated rapid binding of both compounds to tubulin even at 0 degrees C (binding was complete at the earliest times examined), in contrast to the relatively slow and temperature-dependent binding of colchicine. Although the binding of the C. caffrum compounds to tubulin was quite tight, permitting ready isolation of near-stoichiometric amounts of drug-tubulin complex even in the absence of free drug, both CS-A4 and CS-A2 dissociated rapidly from tubulin in the presence of high concentrations of radiolabeled colchicine. Apparent rate constants for drug dissociation from tubulin at 37 degrees C were 3.2 x 10(-3) s-1 for CS-A4, 4.8 x 10(-3) s-1 for CS-A2, and 2.9 x 10(-5) s-1 for colchicine (half-lives of 3.6, 2.4, and 405 min, respectively). Thus, the effectiveness of the C. caffrum compounds as antimitotic agents appears to derive primarily from the rapidity of their binding to tubulin.(ABSTRACT TRUNCATED AT 250 WORDS)
  • Article
    Myricetin, robinetin and luteolin inhibited the mutagenic activity resulting from the metabolic activation of benzo[a]-pyrene and (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]-pyrene by rat liver microsomes. These naturally occurring plant flavonoids and seventeen additional flavonoids and related derivatives with phenolic hydroxyl groups inhibited the mutagenic activity of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), which is an ultimate mutagenic and carcinogenic metabolite of benzo[a]pyrene. Several flavonoids without phenolic hydroxyl groups or with methylated phenolic hydroxyl groups were inactive. The mutagenic activity of 0.05 nmol of BP 7,8-diol-9,10-epoxide-2 towards strain TA 100 of S. typhimurium was inhibited 50% by incubation of the bacteria and the diol-epoxide with myricetin (2 nmol), robinetin (2.5 nmol), luteolin (5 nmol), quercetin (5 nmol), 7-methoxyquercetin (5 nmol), rutin (5 nmol), quercetin (5 nmol), delphinidin chloride (5 nmol), morin (10 nmol), myricitrin (10 nmol), kaempferol (10 nmol), diosmetin (10 nmol), fisetin (10 nmol), or apigenin (10 nmol). Considerably less antimutagenic activity was observed for dihydroquercetin, naringenin, robinin, D-catechin, genistein, kaempferide and chrysin. Pentamethoxyquercetin, tangeretin, nobiletin, 7,8-benzoflavone, 5,6-benzoflavone, and flavone, which lack free phenolic groups, were inactive. The antimutagenic activity of hydroxylated flavonoids results from their direct interaction with B[a]P 7,8-diol-9,10-epoxide-2 since the rate of disappearance of the diol-epoxide from cell-free solutions in 1:9 dioxane:water was markedly stimulated by myricetin, robinetin and quercetin. Myricetin was a highly potent inhibitor of the mutagenic activity of bay-region diol-epoxides of benzo[a]pyrene, dibenzo[a,h]pyrene and dibenzo[a,i]pyrene, but higher concentrations of myricetin were needed to inhibit the mutagenicity of the chemically less reactive benzo[a]pyrene 4,5-oxide and bay region diol-epoxides of benz[a]anthracene, chrysene and benzo[c]phenanthrene.
  • Article
    Among the various flavonoids, rutin and quercetin increased the survival time of mice inoculated with NK/Ly ascites tumor cells. The best results were obtained when the mice were given 2.0 mg rutin twice daily for 8 days. The O-silyl-substituted rutin and quercetin were less effective than rutin or quercetin themselves. Besides rutin, quercetin and morin two other flavonoids, luteolin and pelargonidin also exerted growth inhibitory effects on NK/Ly ascites tumor cells cultures in vitro.
  • Article
    New structural modifications of the marine shell-less mollusk peptide constituent dolastatin 10 (1) have been synthesized, and evaluated against a variety of cancer cell lines and for their ability to inhibit tubulin polymerization. A number of useful structure-activity relationships were uncovered. The most important observation was that the dolaphenine unit of dolastatin 10 could be satisfactorily replaced with a phenethylamine. Peptide 11C, designated auristatin PE, was found to exhibit inhibition of cancer cell growth and tubulin assembly comparable to that of dolastatin 10.
  • Article
    Full-text available
    Consumption of a plant-based diet can prevent the development and progression of chronic diseases that are associated with extensive neovascularization; however, little is known about the mechanisms. To determine whether prevention might be associated with dietary-derived angiogenesis inhibitors, we have fractionated urine of healthy human subjects consuming a plant-based diet and examined the fractions for their abilities to inhibit the proliferation of vascular endothelial cells. Using gas chromatography-mass spectrometry, we showed that one of the most potent fractions contained several isoflavonoids, which we subsequently synthesized. Of all synthetic compounds, the isoflavonoid genistein was the most potent and inhibited endothelial cell proliferation and in vitro angiogenesis at concentrations giving half-maximal inhibition of 5 and 150 microM, respectively. As we have previously demonstrated, genistein concentrations in urine of subjects consuming a plant-based diet are in the micromolar range, while those of subjects consuming a traditional Western diet are lower by a factor of > 30. The high excretion of genistein in urine of vegetarians and our present results suggest that genistein may contribute to the preventive effect of a plant-based diet on chronic diseases, including solid tumors, by inhibiting neovascularization. Thus, genistein may represent a member of a new class of dietary-derived anti-angiogenic compounds.
  • Article
    An in vivo antitumor screening of extracts of Gomphrena martiana indicated positive activity in the petroleum ether extract, and its further bioactivity-directed fractionation resulted in a lipophilic flavonoid fraction. Upon inoculation of various doses of 5,6,7-trisubstituted flavones on two murine tumor lines, Sarcoma 180 and Ehrlich's carcinoma, a decrease of tumor growth was observed. An in vitro KB cultured cell screen indicated cytotoxicity.
  • Article
    Gamma linolenic acid (GLA), a polyunsaturated fatty acid, promoted lipid peroxidation in Raji lymphoma suspension cultures, in a dose (10 microM-100 microM) and time-dependent (4 h-48 h) manner. The increase in lipid peroxidation could be correlated to an increase in cytotoxicity. The plant flavonoids (quercetin, luteolin, butein, rutin) and the fat-soluble components (retinol, retinoic acid, alpha-tocopherol) by themselves did not affect lipid peroxidation in Raji cells. Quercetin, luteolin, retinol, and alpha-tocopherol were able to inhibit cell proliferation significantly. Although GLA only decreased the cytotoxicity of retinol-treated cells, the latter compound was able to block the prooxidative action of GLA by scavenging the free radicals induced by it. Quercetin at 50 and 100 microM exerted equipotent superoxide anion scavenging effects, but at the higher concentration it had no effect on lipid peroxidation. Although the bioactive test compounds are well known natural antioxidants, interestingly, our data showed that their potent cytotoxic actions do not involve free radicals or lipid peroxidation reactions.
  • Article
    Full-text available
    Flavonoids are strong antioxidants that occur naturally in foods and can inhibit carcinogenesis in rodents. Accurate data on population-wide intakes of flavonoids are not available. Here, using data of the Dutch National Food Consumption Survey 1987-1988, we report the intake of the potentially anticarcinogenic flavonoids quercetin, kaempferol, myricetin, apigenin, and luteolin among 4,112 adults. The flavonoid content of vegetables, fruits, and beverages was determined by high-performance liquid chromatography. In all subjects, average intake of all flavonoids combined was 23 mg/day. The most important flavonoid was the flavonol quercetin (mean intake 16 mg/day). The most important sources of flavonoids were tea (48% of total intake), onions (29%), and apples (7%). Flavonoid intake did not vary between seasons; it was not correlated with total energy intake (r = 0.001), and it was only weakly correlated with the intake of vitamin A (retinol equivalents, r = 0.14), dietary fiber (r = 0.21), and vitamin C (r = 0.26). Our use of new analytic technology suggests that in the past flavonoid intake has been overestimated fivefold. However, on a milligram-per-day basis, the intake of the antioxidant flavonoids still exceeded that of the antioxidants beta-carotene and vitamin E. Thus flavonoids represent an important source of antioxidants in the human diet.
  • Article
    Genistein, an isoflavone, is a specific inhibitor of tyrosine kinase and topoisomerase II. However, its effect on cell growth is unknown. Therefore, we examined the effects of genistein on cell growth and cell cycle progression and compared its effects with other flavonoids. Genistein inhibited in a dose-dependent manner the growth of HGC-27 cells derived from human gastric cancer. Flow-cytometric analysis showed that genistein almost completely arrested the cell cycle progression at G2-M. This effect was reversible when genistein was removed from the culture medium. In contrast, other flavonoids such as flavone, luteolin, and the structurally similar daidzein arrested the cell cycle at G1. Consistent with the flow-cytometric analysis, microscopic observation showed that genistein did not increase the mitotic index, which supposes that genistein may arrest the cell cycle at G2 or early M. These results suggest that the G2-M arrest by genistein is a unique effect among flavonoids.
  • Article
    Combretastatin A-4 is a natural product which was isolated from the South African tree Combretum caffrum. In this study, the cytotoxic activity of combretastatin A-4 was tested in radiometric and human tumor cloning assays against eight different tumor cell lines and against 15 patient tumors in the human tumor cloning assay. To test the preferential cytotoxicity of combretastatin A-4 against tumor cells versus non-tumor cells, it was also tested in the radiometric assay against both normal human diploid fibroblasts and human bone marrow cells. Of the eight cell lines used, combretastatin A-4 showed preferential cytotoxicity for six of them. In addition, combretastatin A-4 showed a concentration-dependent cytotoxicity against a variety of human tumors. Based on the data generated in this study, combretastatin A-4 should be further tested in in vivo preclinical models.