Letter to the Editor Integrative Cancer Therapies XX(X) 1–2 © The Author(s) 2010 Reprints and permission: http://www. sagepub.com/journalsPermissions.nav DOI: 10.1177/1534735410378662 http://ict.sagepub.com
Cancer Chemoprevention by 7-Prenyloxycoumarins: A Role for 5-Lipoxygenase Inhibition? Amirhossein Sahebkar, PharmD1, and Mehrdad Iranshahi, PharmD, PhD,1 Dear Editor, Cancer chemoprevention is defined as the use of synthetic, biological, chemical, or natural dietary components to inhibit, delay, or revert the development of cancer in normal or preneoplastic tissue. This strategy is regarded as one of the most encouraging areas in current cancer research. By way of characterization and development of effective and safe chemopreventive agents, natural products from plants and their synthetic derivatives have been extensively explored and are expected to play an important role in this field.1 7-Prenyloxycoumarins are a group of secondary metabolites that are found mainly in plants belonging to the families of Rutaceae and Umbelliferae and particularly in Citrus spp. In the past 2 decades, reports on diverse biological activities of these compounds, have changed the attitude toward them from mere biosynthetic intermediates to potential natural therapeutic agents.2 Recently, promising in vitro and in vivo cancer chemopreventive and anticancer activities have been reported from 4 of the most studied 7-prenyloxycoumarins, namely auraptene,3,4 umbelliprenin,3,5,6 7-isopentenyloxycoumarin,7 and collinin.8 This is especially the case for auraptene, which is regarded as one of the most powerful natural chemopreventive agents against different types of cancers.2 However, the mechanisms responsible for the cancer chemopreventive activity of these compounds are not fully clarified. In a recent preliminary study, we have reported that umbelliprenin (Figure 1) is a potent inhibitor of soybean 5-lipoxygenase enzyme. The IC50 (half maximal inhibitory concentration) value for the mentioned inhibitory activity was 0.0725 mM, which was markedly more than that of caffeic acid as a standard inhibitor of 5-lipoxygenase9 (IC50: 600 mM for soybean 5-lipoxygenase and 3.7 mM for human 5-lipoxygenase). Based on this evidence, it is hypothesized that along with other mechanisms,6,8,10 blocking of the enzyme 5-lipoxygenase may be a plausible mechanism accounting for at least part of the observed chemopreventive activity of umbelliprenin and other 7-prenyloxycoumarins. The rationale for this hypothesis is the mounting evidence from in vitro and in vivo studies, which indicates the overexpression of 5-lipoxygenase and its metabolites in a broad variety of
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Figure 1. Chemical structure of umbelliprenin
cancer cells and tissues, thereby supporting a role for this enzyme in the development and progression of human cancers.11,12 Therefore, 5-lipoxygenase is considered as a new potential target for the prevention and treatment of cancer. In previous studies, promising chemopreventive and anticancer effects have been reported from 5-lipoxygenase inhibitors against various types of cancers, including those of the prostate, lung, pancreas, brain, esophagus, oral cavity, and so on.13,14 To evaluate the aforementioned hypothesis one would need to test the inhibitory effects of these class of compounds against human 5-lipoxygenase enzyme. With positive results, there is also a possibility for the efficacy of these compounds in the treatment of asthma. Regarding the natural origin of these phytochemicals, their presence in edible vegetables and fruits such as Citrus spp., and finally the feasibility of their chemical synthesis,15 these phytoche micals may serve as a new class of chemopreventive and anticancer agents. References 1. Hong WK, Sporn MB. Recent advances in chemoprevention of cancer. Science. 1997;278:1073-1077. 2. Curini M, Cravotto G, Epifano F, Giannone G. Chemistry and biological activity of natural and synthetic prenyloxycoumarins. Curr Med Chem. 2006;13:199-222. 1
Mashhad University of Medical Sciences, Mashhad, Iran
Corresponding Author: Amirhossein Sahebkar, School of Pharmacy, Mashhad University of Medical Sciences, Vakilabad Boulevard, PO Box 91775-1365, Mashhad, Iran Email:
[email protected]
2 3. Iranshahi M, Kalategi F, Rezaee R, et al. Cancer chemopreventive activity of terpenoid coumarins from Ferula species. Planta Med. 2008;74:147-150. 4. Sakata K, Hara A, Hirose Y, Yamada Y. Dietary supplementation of the citrus antioxidant auraptene inhibits N, N-diethylnitrosamine-induced rat hepatocarcinogenesis. Oncology. 2004;66:244-252. 5. Iranshahi M, Sahebkar A, Takasaki M, et al. Cancer chemopreventive activity of the prenylated coumarin, umbelliprenin, in vivo. Eur J Cancer Prev. 2009;18:412-415. 6. Barthomeuf C, Lim S, Iranshahi M, Chollet P. Umbelliprenin from Ferula szowitsiana inhibits the growth of human M4Beu metastatic pigmented melanoma cells through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. Phytomedicine. 2008;15:103-111. 7. Baba M, Jin Y, Mizuno A, et al. Studies on cancer chemoprevention by traditional folk medicines: XXIV. Inhibitory effect of a coumarin derivative, 7-isopentenyloxycoumarin, against tumor-promotion. Biol Pharm Bull. 2002;25:244-246. 8. Kohno H, Suzuki R, Curini M, et al. Dietary administration with prenyloxycoumarins, auraptene and collinin, inhibits colitis-related colon carcinogenesis in mice. Int J Cancer. 2006; 118:2936-2942.
Integrative Cancer Therapies XX(X) 9. Iranshahi M, Askari M, Sahebkar A, Hadjipavlou-Litina D. Evaluation of antioxidant, anti-inflammatory and lipoxygenase inhibitory activities of the prenylated coumarin umbelliprenin. Daru. 2009;17:99-103. 10. Murakami A, Nakamura Y, Tanaka T, et al. Suppression by citrus auraptene of phorbol ester- and endotoxin-induced inflammatory responses: role of attenuation of leukocyte activation. Carcinogenesis. 2000;21:1843-1850. 11. Soumaoro LT, Iida S, Uetake H, et al. Expression of 5lipoxygenase in human colorectal cancer. World J Gastroenterol. 2006;12:6355-6360. 12. Hoque A, Lippman SM, Wu TT, et al. Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: a potential target for prevention. Carcinogenesis. 2005;26:785-791. 13. Ghosh J. Targeting 5-lipoxygenase for prevention and treatment of cancer. Curr Enzyme Inhib. 2008;4:18-28. 14. Chen X, Sood S, Yang CS, et al. Five-lipoxygenase pathway of arachidonic acid metabolism in carcinogenesis and cancer chemoprevention. Curr Cancer Drug Targets. 2006; 6:613622. 15. Askari M, Sahebkar A, Iranshahi M. Synthesis and purification of 7-prenyloxycoumarins and herniarin as bioactive natu-
