Skip to main content
NCBI home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 19;94(1):92–98. doi: 10.1111/j.1349-7006.2003.tb01358.x

Evodiamine, a constituent of Evodiae Fructus, induces anti‐proliferating effects in tumor cells

Xiao Fang Fei 1, Ben Xiang Wang 2, Tei Jin Li 3, Shin‐ichi Tashiro 4, Mutsuhiko Minami 5, De Jun Xing 6, Takashi Ikejima 7,8
PMCID: PMC11160161  PMID: 12708481

Abstract

We found that evodiamine, a major alkaloidal component of Evodiae Fructus (Goshuyu in Japan), inhibited proliferation of several tumor cell lines, but had less effect on human peripheral blood mononuclear cells (PBMC). We used human cervical cancer cells, HeLa, as a model to elucidate the molecular mechanisms of evodiamine‐induced tumor cell death. The results showed that evodiamine induced oligonucleosomal fragmentation of DNA in HeLa cells and increased the activity of caspase‐3, but not that of caspase‐1, in vitro. Both evodiamine‐induced DNA fragmentation and caspase‐3 activity were effectively inhibited by a caspase‐3 inhibitor, z‐DEVD‐fmk (z‐Asp‐Glu‐Val‐Asp‐fmk). In addition, evodiamine increased the expression of the apoptosis inducer Bax, but decreased the expression of the apoptosis suppressor Bcl‐2 in mitochondria. Taken together, our data indicated that evodiamine alters the balance of Bcl‐2 and Bax gene expression and induces apoptosis through the caspase pathway in HeLa cells. (Cancer Sci 2003; 94: 92–98)

References

  • 1. Li SC. 1596 Pen‐tsao Kang Mu. Taipei : National Research Institute of Chinese Medicine; 1976. p. 1064. [Google Scholar]
  • 2. Anonymous . Encyclopedia of Chinese medicine. Shanghai : People's Press, People's Republic of China; 1977. p. 1118. [Google Scholar]
  • 3. Shoji N, Umeyama A, Takemoto T, Kajiwara A, Ohizumi Y. Isolation of evodiamine, a powerful cardiotonic principle, from Evodia rutaecarpa Bentham (Rutaceae). J Pharm Sci 1986; 75: 612–3. [DOI] [PubMed] [Google Scholar]
  • 4. Chang HM, But PPH. Pharmacology and Applications of Chinese Medica, Vol. I. Singapore : World Scientific Publishing; 1987. p. 605. [Google Scholar]
  • 5. Kobayashi Y, Nakano Y, Hoshikuma K, Yokoo Y, Kamiya T. The broncho‐constrictive action of evodiamine, an indoloquinazoline alkaloid isolated from the fruits of Evodia rutaecarpa, on guinea‐pig isolated bronchus: possible involvement of vanilloid receptors. Planta Med 2000; 66: 526–30. [DOI] [PubMed] [Google Scholar]
  • 6. Lin H, Tsai SC, Chen JJ, Chiao YC, Wang SW, Wang GJ, Chen CF, Wang PS. Effect of evodiamine on the secretion of testosterone in rat testicular interstitial cells. Metabolism 1999; 48: 1532–5. [DOI] [PubMed] [Google Scholar]
  • 7. Chiou WE, Chou CJ, Shum AY, Chen CF. The vasorelaxant effect of evodiamine in rat isolated mesenteric arteries: mode of action. Eur J Pharmacol 1992; 215: 277–83. [DOI] [PubMed] [Google Scholar]
  • 8. Chiou WE, Liao JF, Chen CF. Comparative study of the vasodilatory effects of three quinazoline alkaloids isolated from Evodia rutaecarpa . J Nat Prod 1996; 59: 374–8. [DOI] [PubMed] [Google Scholar]
  • 9. Yoshizumi M, Houchi H, Ishimura Y, Hirose M, Kitagawa T, Tsuchiya K, Minakuchi K, Tamaki T. Effect of evodiamine on catecholamine secretion from bovine adrenal medulla. J Med Invest 1997; 44: 79–82. [PubMed] [Google Scholar]
  • 10. Yamahara J, Yamada T, Kitani T, Naitoh Y, Fujimura H. Antianoxic action of evodiamine, an alkaloid in Evodia rutaecarpa fruit. J Ethnopharmacol 1989; 27: 185–92. [DOI] [PubMed] [Google Scholar]
  • 11. Chiou WE, Sung YJ, Liao JF, Shum AJ, Chen CF. Inhibitory effect of dehy‐droevodiamine and evodiamine on nitric oxide production in cultured murine macrophages. J Nat Prod 1997; 60: 708–11. [DOI] [PubMed] [Google Scholar]
  • 12. Matsuda H, Wu JX, Tanaka T, Iinuma M, Kubo M. Antinociceptive activities of 70% methanol extract of evodiae fructus and its alkaloidal components. Biol Pharm. Bull 1997; 20: 243–8. [DOI] [PubMed] [Google Scholar]
  • 13. Tsai TH, Lee TF, Chen CF, Wang LC. Thermoregulatory effects of alkaloids isolated from Wu‐chu‐yu in afebrile and febrile rats. Pharmacol Biochem Behav 1995; 50: 293–8. [DOI] [PubMed] [Google Scholar]
  • 14. Kano Y, Zong QN, Komatsu K. Pharmacological properties of galenical preparations. XIV. Body temperature retaining effect of the Chinese traditional medicine, “goshuyu‐to” and component crude drugs. Chem Pharm Bull; ( Tokyo ), 1991; 39: 690–2. [DOI] [PubMed] [Google Scholar]
  • 15. King CL, Kong YC, Wong NS, Yeung HW, Fong HH, Sankawa U. Uterotonic effect of Evodia rutaecarpa alkaloids. J Nat Prod 1980; 43: 577–82. [DOI] [PubMed] [Google Scholar]
  • 16. Parkin DM, Laara E, Muir CS. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 1988; 41: 184–97. [DOI] [PubMed] [Google Scholar]
  • 17. Kerr JFR, Winterford CM, Harmon BV. Apoptosis: its significance in cancer and cancer therapy. Cancer 1994; 73: 2013–26. [DOI] [PubMed] [Google Scholar]
  • 18. Oyaizu N, Pahwa S. Role of apoptosis in HIV disease pathogenesis. J Clin Immunol 1995; 15: 217–31. [DOI] [PubMed] [Google Scholar]
  • 19. Han DKM, Haudenschild CC, Hong MK, Tinkle BT, Leon MB, Liau G. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am J Pathol 1995; 147: 267–77. [PMC free article] [PubMed] [Google Scholar]
  • 20. Hickmann JA. Apoptosis induced by anticancer drugs. Cancer Metastasis Rev 1992; 11: 121–39. [DOI] [PubMed] [Google Scholar]
  • 21. Chen Z, Naito M, Mashima T, Tsuruo T. Activation of actin‐cleavable interleukin 1β‐converting enzyme (ICE) family protease CPP32 during chemotherapeutic agent‐induced apoptosis in ovarian carcinoma cells. Cancer Res 1996; 56: 5224–9. [PubMed] [Google Scholar]
  • 22. Schlegel J, Peters I, Orrenius S, Miller DK, Thornberry NA, Yamin TT, Nicholson DW. CPP32/apopain is a key interleukin‐lβ‐converting enzyme‐like protease involved in Fas‐mediated apoptosis. J Biol Chem 1996; 271: 1841–4. [DOI] [PubMed] [Google Scholar]
  • 23. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J. Human ICE/CED‐3 protease nomenclature. Cell 1996; 87: 171. [DOI] [PubMed] [Google Scholar]
  • 24. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl‐2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74: 609–19. [DOI] [PubMed] [Google Scholar]
  • 25. Hockenbery D, Nunez G, Milliman C, Schreitber RD, Korsmeyer S. Bcl‐2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990; 348: 334–6. [DOI] [PubMed] [Google Scholar]
  • 26. Thornberry NA, Lazebnik Y. Caspase: enemies within. Science 1998; 281: 1312–6. [DOI] [PubMed] [Google Scholar]
  • 27. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA. Identification and inhibition of the ICE/CED‐3 protease necessary for mammalian apoptosis. Nature 1995; 376: 37–43. [DOI] [PubMed] [Google Scholar]
  • 28. Ohta T, Kinoshita T, Naito M, Nozaki T, Masutani M, Tsuruo T, Miyajima A. Requirement of the caspase‐3/CPP32 protease cascade for apoptotic death following cytokine deprivation in hematopoietic cells. J Biol Chem 1997; 272: 23111–6. [DOI] [PubMed] [Google Scholar]
  • 29. Enari M, Talanian RV, Wong WW, Nagata S. Sequential activation of ICE‐like and CPP32‐like proteases during Fas‐mediated apoptosis. Nature 1996; 380: 723–6. [DOI] [PubMed] [Google Scholar]
  • 30. Los M, Van DCM, Penning LC, Schenk H, Westendorp M, Baeuerle PA, Droqe W, Krammer PH, Fiers W, Schulze OK. Requirement of an ICE/ CED‐3 protease for Fas/APO‐1 mediated apoptosis. Nature 1995; 375: 81–3. [DOI] [PubMed] [Google Scholar]
  • 31. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf‐1, a human protein homologous to C. elegans CED‐4, participates in cytochrome c‐dependent activation of caspase‐3. Cell 1997; 90: 405–13. [DOI] [PubMed] [Google Scholar]
  • 32. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X. Cytochrome c and dATP‐dependent formation of Apaf‐1/caspase‐9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479–89. [DOI] [PubMed] [Google Scholar]
  • 33. Kroemer G, Petit P, Zamzami N, Vayssiere JL, Mignotte B. The biochemistry of programmed cell death. FASEB J 1995; 9: 1277–87. [DOI] [PubMed] [Google Scholar]
  • 34. Hengartner MO, Horvitz HR. C. elegans cell survival gene ced‐9 encodes a functional homolog of the mammalian proto‐oncogene bcl‐2. Cell 1994; 76: 665–76. [DOI] [PubMed] [Google Scholar]
  • 35. Hockenbery D, Nunez G, Milliman C, Schreitber RD, Korsmeyer S. Bcl‐2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990; 348: 334–6. [DOI] [PubMed] [Google Scholar]
  • 36. Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, Perucho M. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275: 967–9. [DOI] [PubMed] [Google Scholar]
  • 37. Xu DM. Chemistry of Ginseng. In: Wang BX, editor. Ginseng Research , Tianjin : Scientific and Technical Press; 1984. p. 51–68. [Google Scholar]
  • 38. Itoh S, Hattori T, Hayashi H, Mizutani Y, Todo M, Takii T, Yang D, Lee JC, Matsufuji S, Murakami Y, Chiba T, Onozaki K. Antiproliferative effect of IL‐1 is mediated by p38 mitogen‐activated protein kinase in human melanoma cell A375. J Immunol 1999; 162: 7434–40. [PubMed] [Google Scholar]
  • 39. Yano H, Mizoguchi M, Fukuda K, Haramaki M, Ogasawara S, Momosaki S, Kojiro M. The herbal medicine sho‐saiko‐to inhibits proliferation of cancer cell lines by inducing apoptosis and arrest at the G0/G1 phase. Cancer Res 1994; 54: 448–54. [PubMed] [Google Scholar]
  • 40. Lamarre D, Talbot B, De MG, Laplante C, Leduc Y, Mazen A, Poirier GG. Structural and functional analysis of poly (ADP‐ribose) polymerase: an immunological study. Biochim Biophys Acta 1998; 950: 147–60. [DOI] [PubMed] [Google Scholar]
  • 41. Rao L, White E. Bcl‐2 and ICE family of apoptotic regulators: marking a connection. Curr Opin Genet Dev 1997; 7: 52–8. [DOI] [PubMed] [Google Scholar]
  • 42. Takahashi A, Earnshaw WC. ICE‐related proteases in apoptosis. Curr Opin Genet Dev 1996; 6: 50–5. [DOI] [PubMed] [Google Scholar]
  • 43. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Sheuchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM. FLICE, a novel FADD‐homologous ICE/CED3 like protease, is recruited to the CD95 (Fas/APO‐1) death‐inducing signaling complex. Cell 1996; 85: 817–27. [DOI] [PubMed] [Google Scholar]
  • 44. Villa P, Kaufmann SH, Earnshaw WC. Caspases and caspase inhibitors. Trends Biochem. Sci 1997; 22: 388–93. [DOI] [PubMed] [Google Scholar]
  • 45. Golstein P. Controlling cell death. Science 1997; 275: 1081–2. [DOI] [PubMed] [Google Scholar]
  • 46. Boulakia CA, Chen G, Ng FWH, Teodoro JG, Branton PE, Nicholson DW, Poirier GG, Shore GC. Bcl‐2 and adenovirus EIB 19kDA protein prevent EIA‐induced processing of CPP32 and cleavage of poly (ADP‐ribose) polymerase. Oncogene 1996; 12: 529–35. [PubMed] [Google Scholar]
  • 47. Erhardt P, Cooper GM. Activation of rhe CPP32 apoptotic protease by distinct signaling pathways with differential sensitivity to Bcl‐xL. J Biol Chem 1996; 271: 17601–4. [DOI] [PubMed] [Google Scholar]
  • 48. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jone DP, Wang X. Prevention of apoptosis by Bcl‐2: release of cytochrome c from mitochondria blocked. Science 1997; 275: 1129–32. [DOI] [PubMed] [Google Scholar]
  • 49. Perlman H, Zhang XJ, Chen MW, Walsh K, Buttyan R. An elevated bax/bcl‐2 ratio corresponds with the onset of prostate epithelial cell apoptosis. Cell Death Differ 1999; 6: 48–54. [DOI] [PubMed] [Google Scholar]
  • 50. Fanidi A, Harrington EA, Evan GI. Cooperative interaction between c‐myc and bcl‐2 proto‐oncogenes. Nature 1992; 359: 554–6. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES