The enhancement of vincristine cytotoxicity by combination with feselol (original) (raw)
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7-Prenyloxycoumarins are a group of secondary metabolites found mainly in plants belonging to the families Rutaceae and Apiaceae. Auraptene, umbelliprenin (UM), and 7-isopentenyloxycoumarin are some examples of prenylated coumarins. UM occurs in various edible plant species including celery, coriander, angelica, lemon, and particularly, Ferula species. Although UM was isolated more than 50 years ago, its biological activities have been studied since the last two decades. Besides anticancer activities, biological activities including anti-inflammatory, antioxidant, and antileishmanial activities have been reported from this natural compound. The present mini-review deals with the biological activities and mechanism of actions reported for UM.
Umbelliferone and Esculetin: Inhibitors or Substrates for Polyphenol Oxidases?
Biological & Pharmaceutical Bulletin, 2008
Hydroxycoumarins (ar-hydroxy-1,2-benzopyrones) are lactone derivatives of 4-coumaric (p-coumaric) acid. In higher plants these molecules are synthesized via the phenylpropanoid pathway 1) beginning from an unusual hydroxylation in the ortho position of the acid side chain (Chart 1). The next step is the trans/cis isomerization of the double bond of this 2,4-dihydroxycinnamic acid. The subsequent lactonization leads to the formation of 7-hydroxycoumarin, trivial name umbelliferone. Other coumarin derivatives such as 6,7-dihydroxycoumarin (trivial name esculetin) and 7hydroxy-6-methoxycoumarin (scopoletin) seem to originate from the addition of oxygenated substituents to the aromatic ring of umbelliferone rather than from a cinnamic acid derivative. 2) Coumarins are widely distributed in higher plants and are especially abundant in Umbelliferae and Rutaceae families. In the past few years, coumarins received much attention for their diverse bioactivities (reviewed in Borges et al.). 4) Some coumarins from natural sources have been also used as therapeutic agents in humans. Polyphenol oxidase (PPO) is a widespread copper-enzyme, containing two copper ions, that catalyzes the ortho-hydroxylation of monophenols to the corresponding ortho-diphenols (catechols) and the oxidation of catechols to the corresponding ortho-quinones. 6) Enzyme nomenclature differentiates between tyrosinase, phenolase, phenol oxidase, polyphenol oxidase, and catechol oxidase, depending on the particular source and also on the authors who have described any particular enzyme. The term tyrosinase is usually adopted for the microorganism, animal, and human enzyme, and refers to the "typical" substrate, tyrosine, while PPO mostly refers to the plant enzyme. PPO is perhaps the most suitable general Recently, an interesting debate arose about the nature (substrate versus inhibitor) of esculetin, a coumarin derivative, for mushroom polyphenol oxidase (PPO). The present study examined the behavior of PPOs preparations from fungal and plant origin towards esculetin as a substrate. Both enzymes were able to oxidize esculetin though at a slow rate. A higher sensitivity was reached when the assay was performed in the presence of 3methyl-2-benzothiazolinone hydrazone (MBTH) even with a lower amount of PPO. These observations unambiguously confirmed that esculetin has to be considered a substrate for mushroom polyphenol oxidase. The oxidation of esculetin was also demonstrated for the first time by a fungal laccase. This should be taken into account because some mushroom PPO preparations could exert contaminant laccase activity. In addition, a PPO preparation from Ferula communis was demonstrated to use esculetin as a substrate. Umbelliferone, the monophenolic precursor of esculetin along the phenylpropanoid pathway, behaved as a competitive inhibitor for the monophenolase activity of mushroom PPO with a K i value410.0؍ mM. This is worth a mention because only a few couples of mono-and corresponding o-diphenol show such opposite behavior towards PPO. A possible role of PPO in the esculetin fate along biosynthesis pathway of coumarin derivatives is also discussed.
Assessment of the Antitumor Potential of Umbelliprenin, a Naturally Occurring Sesquiterpene Coumarin
Cancer is one of the greatest causes of mortality worldwide. The prevalence rates of different types of cancer is increasing around the world as well. Limitations in chemotherapy and radiotherapy, owing to multiple side effects including cytotoxic effects of antitumor compounds on normal cells as well as the development of resistance to these treatment options in patients, create a serious threat to successful treatment of cancer. The use of natural compounds to prevent and treat cancers has been found to be quite effective, with fewer adverse effects found in patients. Umbelliprenin (UMB) is a naturally occurring sesquiterpene compound found in Ferula species and recently in Artemisia absinthium. Many studies have highlighted the antitumor potential of UMB in different cancer cell lines as well as in animal models. UMB exerts its anticancer actions by regulating extrinsic and intrinsic apoptotic pathways; causing inhibition of the cell cycle at the G0/G1 phase; and attenuating migration and invasion by modulating the Wnt signaling, NF-kB, TGFβ, and Fox3 signaling pathways. UMB also affects the key hallmarks of tumor cells by attenuating tumor growth, angiogenesis, and metastasis. This review provides an insight into the role of UMB as a potential antitumor drug for different malignancies and highlights the signaling cascades affected by UMB treatment in diverse tumor cell lines and preclinical models.
Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action
Cells
Despite significant technological advancements in conventional therapies, cancer remains one of the main causes of death worldwide. Although substantial progress has been made in the control and treatment of cancer, several limitations still exist, and there is scope for further advancements. Several adverse effects are associated with modern chemotherapy that hinder cancer treatment and lead to other critical disorders. Since ancient times, plant-based medicines have been employed in clinical practice and have yielded good results with few side effects. The modern research system and advanced screening techniques for plants’ bioactive constituents have enabled phytochemical discovery for the prevention and treatment of challenging diseases such as cancer. Phytochemicals such as vincristine, vinblastine, paclitaxel, curcumin, colchicine, and lycopene have shown promising anticancer effects. Discovery of more plant-derived bioactive compounds should be encouraged via the exploitation...
Proceedings of the Nutrition Society, 2007
Epidemiological studies showing a protective effect of diets rich in fruits and vegetables against cancer have focused attention on the possibility that biologically-active plant secondary metabolites exert anti-carcinogenic activity. This huge group of compounds, now collectively termed ‘phytochemicals’, provides much of the flavour and colour of edible plants and the beverages derived from them. Many of these compounds also exert anti-carcinogenic effects in animal models of cancer, and much progress has been made in defining their many biological activities at the molecular level. Such mechanisms include the detoxification and enhanced excretion of carcinogens, the suppression of inflammatory processes such as cyclooxygenase-2 expression, inhibition of mitosis and the induction of apoptosis at various stages in the progression and promotion of cancer. However, much of the research on phytochemicals has been conducted in vitro, with little regard to the bioavailability and metabol...
ANTI-CANCER AGENTS DERIVED FROM PLANT AND DIETARY SOURCES: A REVIEW
Cancer is a disease of deregulated cellular behavior. Acquisition of oncogenic attributes, loss of tumor suppressive functions, evasion of physiological tissue architecture and interactions with the cellular microenvironment enable malignant cells to escape the mechanisms of normal cellular homeostasis in an organism. Cancer cells are therefore able to sustain unlimited proliferation, to thrive under conditions that preclude normal cell survival, and to spread to distant sites through the process of metastasis. Natural products are important sources of new anticancer drugs, new drug leads and new chemical entities. The plant based drug discovery resulted mainly in the development of anticancer agents including plants (vincristine, vinblastine, paclitaxel, etoposide, camptothecin, topotecan and irinotecan). Beside this there is numerous agents identified from fruits and vegetables can used in anticancer therapy. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. In this review active principle derived from natural products are offering a great opportunity to evaluate not only totally new chemical classes of anticancer agents, but also novel lead compound and potentially relevant mechanisms of action.
Evaluation of anticancer efficacy of umbelliferone with or without piperine
Phytocompounds are pleotropic in their function and preferentially target cancer cells without altering normal cells. In the present study, MTT [3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide] assay was conducted on MCF-7 and MDA-MB-231 cell lines at 48h incubation to determine percent cell viability. The IC50 values of umbelliferone and piperine for MCF-7 were 15.56 and 17.83μM, respectively. Likewise, IC50 values of umbelliferone and piperine for MDA-MB-231 were 10.31 and 14.28 μM, respectively. A combination of umbelliferone (IC25) and piperine (IC25) on MDA-MB-231 and MCF-7 showed percent cell viability of 8.24±0.01 and 15.12±0.01, respectively. This study suggests that the cytotoxicity of umbelliferone and piperine was dose-dependent. The in vitro cytotoxicity potential in terms of percent cell viability, early apoptosis, late apoptosis and G2M phase arrest of umbelliferone alone and in combination with piperine proved to be more effective on MDA-MB-231 cells.
Clinical Biochemistry, 2011
Metastatic malignant melanoma have a bad prognosis (median survival: 6-8 months) mainly due to the development of lung, hepatic and brain metastases. In this study we have used the resazurin reduction test and FACS analysis to assess the cytostatic and cytotoxic effect of umbelliprenin from Ferula szowitsiana (Apiaceae) on human solid cancer cells and human primary fibroblasts. We have observed that the cell susceptibility to umbelliprenin decreases in the order M4Beu (metastatic pigmented malignant melanoma)4A549 (nonsmall cell lung carcinoma)EPC3 (androgenresistant prostate carcinoma)4PA1 (ovary teratocarcinoma)4human primary fibroblastsEMCF7 (breast adenocarcinoma)4DLD1 (colon adenocarcinoma). M4Beu cell-proliferation is inhibited through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. The finding that the cytotoxic effect of umbelliprenin is markedly more pronounced in M4Beu cells than in primary fibroblasts, suggests a therapeutic margin. As M4Beu cell proliferation is more potently inhibited by umbelliprenin (IC 50 12.3 mM) than by the citrus coumarin auraptene (7-geranyloxycoumarin, IC 50 17.1 mM) previously reported capable of inhibiting the prevalence of lung metastasis in mice bearing B16BL6 murine melanoma, our data suggest that umbelliprenin orally administered and foods and folk medicines containing this coumarin, may afford protection against the development and early recurrence of malignant melanoma. In vivo investigations are needed to test these hypotheses.