• Omid Gholami Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
  • Jamal Shamsara Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran


Umbelliprenin and auraptene structurally belong to the class of coumarins. Umbelliprenin can be synthesized chemically or extracted by maceration at room temperature. Various biological effects for both umbel lip renin and auraptene have been reported. One of their most important effects is cytotoxicity. This finding has increased interest in the application of umbelliprenin and auraptene as novel chemotherapeutic agents. In several studies, umbelliprenin and auraptene were successfully evaluated for anti-cancer effect. Moreover, mechanistic studies have attempted to find the mechanism of action of umbelliprenin and auraptene. In this review, we describe the cytotoxic effects of umbelliprenin and auraptene and compare them with each other. Umbelliprenin and auraptene share some cytotoxic and apoptotic induction properties but have differences in the suggested mechanisms.


Keywords: Apoptosis, Auraptene, Cytotoxicity, Cancer, Umbelliprenin


Download data is not yet available.


1. Shakeri A, Iranshahy M, Iranshahi M. Biological properties and molecular targets of umbelliprenin-a mini-review. J Asian Nat Prod Res 2014;16:884-9.
2. Safdari H, Neshani A, Sadeghian A, Ebrahimi M, Iranshahi M, Sadeghian H. Potent and selective inhibitors of class A beta-lactamase: 7-prenyloxy coumarins. J Antibiot (Tokyo) 2014; 67:373-7.
3. Jung CG, Uhm KO, Horike H, Kim MJ, Misumi S, Ishida A, et al. Auraptene increases the production of amyloid-beta via c-Jun N-terminal kinase-dependent activation of gamma-secretase. J Alzheimers Dis 2015;43:1215-28.
4. Nakamura M, Suzuki T, Takagi M, Tamura H, Masuda T. Stimulation of phosphorylation of ERK and CREB by phellopterin and auraptene isolated from Citrusjunos. Nat Prod Commun 2014;9:1491-4.
5. Zamani Taghizadeh Rabe S, Iranshahi M, Mahmoudi M. In vitro anti-inflammatory and immunomodulatory properties of umbelliprenin and methyl galbanate. J Immuno toxicol 2015;25:1-8.
6. Li G, Li X, Cao L, Zhang L, Shen L, Zhu J, et al. Sesquiterpene coumarins from seeds of Ferula sinkiangensis. Fitoterapia 2015;103:222-6.
7. Abu-Mustafa EA, el-Bay FK, Fayez MB. Natural coumarins. XII. Umbelliprenin, a constituent of ammi majus L. fruits. J Pharm Sci 1971;60:788-9.
8. Iranshahi M, Arfa P, Ramezani M, Jaafari MR, Sadeghian H, Bassarello C, et al. Sesquiterpene coumarins from Ferula szowitsiana and in vitro antileishmanial activity of 7-prenyloxycoumarins against promastigotes. Phytochemistry 2007;68:554-61.
9. Iranshahi M, Sahebkar A, Takasaki M, Konoshima T, Tokuda H. Cancer chemo preventive activity of the prenylated coumarin, umbelliprenin, in vivo. Eur J Cancer Prev 2009;18:412-5.
10. Barthomeuf C, Lim S, Iranshahi M, Chollet P. Umbelliprenin from Ferula szowitsiana inhibits the growth of human M4Beu metastatic pigmented malignant melanoma cells through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. Phytomedicine 2008;15:103-11.
11. Ziai SA, Gholami O, Iranshahi M, Zamani AH, Jeddi-Tehrani M. Umbelliprenin induces apoptosis in CLL cell lines. Iran J Pharm Res 2012;11:653-9.
12. Gholami O, Jeddi-Tehrani M, Iranshahi M, Zarnani AH, Ziai SA. Umbelliprenin from ferula szowitsiana activates both intrinsic and extrinsic pathways of apoptosis in jurkat T-CLL cell line. Iran J Pharm Res 2013;12:371-6.
13. Gholami O, Jeddi-Tehrani M, Iranshahi M, Zarnani AH, Ziai SA. Mcl-1 Is Up regulated by prenylated coumarin, Umbelliprenin in jurkat cells. Iran J Pharm Res 2014;13:1385-90.
14. Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 2003;426:671-6.
15. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S, et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemo response. Blood 1998;91:3379-89.
16. Khorramizadeh MR, Esmail-Nazari Z, Zarei-Ghaane Z, Shakibaie M, Mollazadeh-Moghaddam K, Iranshahi M, et al. Umbelliprenin-coated Fe3O4 magnetite nanoparticles: antiproliferation evaluation on human Fibrosarcoma cell line (HT-1080). Mater Sci Eng Proc Conf 2010;30:1038-42.
17. Khaghanzadeh N, Mojtahedi Z, Ramezani M, Erfani N, Ghaderi A. Umbelliprenin is cytotoxic against QU-DB large cell lung cancer cell line but anti-proliferative against A549 adenocarcinoma cells. Daru 2012;20:69.
18. Soltani F, Mosaffa F, Iranshahi M, Karimi G, Malekaneh M, Haghighi F, et al. Evaluation of antigenotoxicity effects of umbelliprenin on human peripheral lymphocytes exposed to oxidative stress. Cell Biol Toxicol 2009;25:291-6.
19. Satoh Y, Tashiro S, Satoh M, Fujimoto Y, Xu JY, Ikekawa T. [Studies on the bioactive constituents of aurantii fructus immaturus]. Yakugaku Zasshi 1996;116:244-50.
20. Murakami A, Nakamura Y, Tanaka T, Kawabata K, Takahashi D, Koshimizu K, et al. Suppression by citrus auraptene of phorbol ester-and endotoxin-induced inflammatory responses: role of attenuation of leukocyte activation. Carcinogenesis 2000;21:1843-50.
21. Jun DY, Kim JS, Park HS, Han CR, Fang Z, Woo MH, et al. Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or-independent caspase cascade. Carcinogenesis 2007;28:1303-13.
22. Min BK, Hyun DG, Jeong SY, Kim YH, Ma ES, Woo MH. A new cytotoxic coumarin, 7-[(E)-3',7'-dimethyl-6'-oxo-2',7'-octadienyl] oxy coumarin, from the leaves of Zanthoxylum schinifolium. Arch Pharm Res 2011;34:723-6.
23. Tanaka T, Kawabata K, Kakumoto M, Matsunaga K, Mori H, Murakami A, et al. Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis by citrus auraptene in rats. Carcinogenesis 1998;19:425-31.
24. Kawabata K, Tanaka T, Yamamoto T, Hara A, Murakami A, Koshimizu K, et al. Suppression of N-nitroso methyl benzylamine-induced rat esophageal tumorigenesis by dietary feeding of auraptene. J Exp Clin Cancer Res 2000;19:45-52.
25. Tanaka T, Kawabata K, Kakumoto M, Hara A, Murakami A, Kuki W, et al. Citrus auraptene exerts dose-dependent chemo preventive activity in rat large bowel tumorigenesis: the inhibition correlates with suppression of cell proliferation and lipid peroxidation and with induction of phase II drug-metabolizing enzymes. Cancer Res 1998;58:2550-6.
26. Mori H, Niwa K, Zheng Q, Yamada Y, Sakata K, Yoshimi N. Cell proliferation in cancer prevention; effects of preventive agents on estrogen-related endometrial carcinogenesis model and on an in vitro model in human colorectal cells. Mutat Res 2001;480-481:201-7.
27. Hayashi K, Suzuki R, Miyamoto S, Shin-Ichiroh Y, Kohno H, Sugie S, et al. Citrus auraptene suppresses azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db mice. Nutr Cancer 2007;58:75-84.
28. Tanaka T, de Azevedo MB, Duran N, Alderete JB, Epifano F, Genovese S, et al. Colorectal cancer chemoprevention by 2 beta-cyclodextrin inclusion compounds of auraptene and 4'-geranyl oxy ferulic acid. Int J Cancer 2010;126:830-40.
29. Epifano F, Genovese S, Miller R, Majumdar AP. Auraptene and its effects on the re-emergence of colon cancer stem cells. Phytother Res 2013;27:784-6.
30. Kitano M, Wanibuchi H, Kikuzaki H, Nakatani N, Imaoka S, Funae Y, et al. Chemo preventive effects of coumaperine from pepper on the initiation stage of chemical hepatocarcinogenesis in the rat. Jpn J Cancer Res 2000;91:674-80.
31. Sakata K, Hara A, Hirose Y, Yamada Y, Kuno T, Katayama M, et al. Dietary supplementation of the citrus antioxidant auraptene inhibits N, N-diethylnitrosamine-induced rat hepato-carcino-genesis. Oncology 2004;66:244-52.
32. Tanaka T, Kohno H, Murakami M, Kagami S, El-Bayoumy K. Suppressing effects of dietary supplementation of the organoselenium 1,4-phenylenebis(methylene)selenocyanate and the citrus antioxidant auraptene on lung metastasis of melanoma cells in mice. Cancer Res 2000;60:3713-6.
33. Tang M, Ogawa K, Asamoto M, Hokaiwado N, Seeni A, Suzuki S, et al. Protective effects of citrus nobiletin and auraptene in transgenic rats developing adenocarcinoma of the prostate (TRAP) and human prostate carcinoma cells. Cancer Sci 2007;98:471-7.
34. Krishnan P, Yan KJ, Windler D, Tubbs J, Grand R, Li BD, et al. Citrus auraptene suppresses cyclin D1 and significantly delays N-methyl nitrosourea-induced mammary carcinogenesis in female sprague-dawley rats. BMC Cancer 2009;9:259.
35. Zheng Q, Hirose Y, Yoshimi N, Murakami A, Koshimizu K, Ohigashi H, et al. Further investigation of the modifying effect of various chemopreventive agents on apoptosis and cell proliferation in human colon cancer cells. J Cancer Res Clin Oncol 2002;128:539-46.
36. Kohno H, Suzuki R, Curini M, Epifano F, Maltese F, Gonzales SP, et al. Dietary administration with prenyl oxy coumarins, auraptene, and collinin, inhibits colitis-related colon carcinogenesis in mice. Int J Cancer 2006;118:2936-42.
37. Krishnan P, Kleiner-Hancock H. Effects of auraptene on IGF-1 stimulated cell cycle progression in the human breast cancer cell line, MCF-7. Int J Breast Cancer 2012. [Article in Press]
38. Murakami A, Kuki W, Takahashi Y, Yonei H, Nakamura Y, Ohto Y, et al. Auraptene, a citrus coumarin, inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in ICR mouse skin, possibly through suppression of superoxide generation in leukocytes. Jpn J Cancer Res 1997;88:443-52.
39. Murakami A, Shigemori T, Ohigashi H. Zingiberaceous and citrus constituents, 1'-acetoxychavicol acetate, zerumbone, auraptene, and nobiletin, suppress lipopolysaccharide-induced cyclo-oxygenase-2 expression in RAW264.7 murine macrophages through different modes of action. J Nutr 2005;135:2987S-92S.
40. Murakami A, Ohigashi H. Cancer-preventive anti-oxidants that attenuate free radical generation by inflammatory cells. Biol Chem 2006;387:387-92.
41. Onuma K, Suenaga Y, Sakaki R, Yoshitome S, Sato Y, Ogawara S, et al. Development of a quantitative bioassay to assess preventive compounds against inflammation-based carcino-genesis. Nitric Oxide 2011;25:183-94.
42. Kawabata K, Murakami A, Ohigashi H. Citrus auraptene targets translation of MMP-7 (matrilysin) via ERK1/2-dependent and mTOR-independent mechanism. FEBS Lett 2006;580:5288-94.
43. Nabekura T, Yamaki T, Kitagawa S. Effects of chemo preventive citrus phytochemicals on human P-glycoprotein and multidrug resistance protein 1. Eur J Pharmacol 2008;600:45-9.
44. de Medina P, Genovese S, Paillasse MR, Mazaheri M, Caze-Subra S, Bystricky K, et al. Auraptene is an inhibitor of cholesterol esterification and a modulator of estrogen receptors. Mol Pharmacol 2010;78:827-36.
45. Li J, Mahdi F, Du L, Jekabsons MB, Zhou YD, Nagle DG. Semisynthetic studies identify mitochondrial poisons from botanical dietary supplements--geranyl oxy coumarins from Aegle marmelos. Bioorg Med Chem 2013;21:1795-803.
576 Views | 697 Downloads
How to Cite
Gholami, O., and J. Shamsara. “COMPARISON OF THE CYTOTOXIC EFFECTS OF UMBELLIPRENIN AND AURAPTENE”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 8, no. 1, Nov. 2015, pp. 1-4,
Review Article(s)