Planta Med 2007; 73(11): 1192-1194
DOI: 10.1055/s-2007-981597
Pharmacology
Letter
© Georg Thieme Verlag KG Stuttgart · New York

Induction of Apoptosis and Regulation of the MAPK Pathway by Ursolic Acid in Human Leukemia K562 Cells

Xiao-Shan Liu1 , Jikai Jiang1
  • 1Center for Molecular Biology, School of Medicine, Shantou University, P. R. China
Further Information

Publication History

Received: April 5, 2007 Revised: July 10, 2007

Accepted: July 17, 2007

Publication Date:
31 August 2007 (online)

Abstract

Ursolic acid (UA) is a pentacyclic triterpene acid naturally occurring in a number of foods and medicinal plants. It is one of the most promising chemopreventive agents and has been reported to induce apoptosis in many cancer cells. Here, we report that treatment with UA induces apoptosis in human leukemia K562 cells and down-regulates protein levels of bcl-xL. Treatment also increases phospho-JNK in a dose- and time-dependent manner but does not alter phospho-Erk1/2 and phospho-P38. These results suggest that JNK may participate in UA-induced apoptosis in K562 cells.

References

  • 1 Lee K H, Lin Y M, Wu T S, Zhang D C, Yamagishi T, Hayashi T. et al . The cytotoxic principles of Prunella vulgaris, Psychotria serpens, and Hyptis capitata: ursolic acid and related derivatives.  Planta Med. 1988;  54 308-11.
  • 2 Rios M Y, Gonzalez-Morales A, Villarreal M L. Sterols, triterpenes and biflavonoids of Viburnum jucundum and cytotoxic activity of ursolic acid.  Planta Med. 2001;  67 683-4.
  • 3 Baek J H, Lee Y S, Kang C M, Kim J A, Kwon K S, Son H C. et al . Intracellular Ca2+ release mediates ursolic acid-induced apoptosis in human leukemic HL-60 cells.  Int J Cancer. 1997;  73 725-8.
  • 4 Es-Saady D, Simon A, Jayat-Vignoles C, Chulia A J, Delage C. MCF-7 cell cycle arrested at G1 through ursolic acid, and increased reduction of tetrazolium salts.  Anticancer Res. 1996;  16 481-6.
  • 5 Es-Saady D, Simon A, Ollier M, Maurizis J C, Chulia A J, Delage C. Inhibitory effect of ursolic acid on B16 proliferation through cell cycle arrest.  Cancer Lett. 1996;  106 193-7.
  • 6 Satomi Y, Nishino H, Shibata S. Glycyrrhetinic acid and related compounds induce G1 arrest and apoptosis in human hepatocellular carcinoma HepG2.  Anticancer Res. 2005;  25 4043-7.
  • 7 Choi Y H, Baek J H, Yoo M A, Chung H Y, Kim N D, Kim K W. Induction of apoptosis by ursolic acid through activation of caspases and downregulation of c-IAPs in human prostate epithelial cells.  Int J Oncol. 2000;  17 565-71.
  • 8 Urech K, Scher J M, Hostanska K, Becker H. Apoptosis inducing activity of viscin, a lipophilic extract from Viscum album L.  J Pharm Pharmacol. 2005;  57 101-9.
  • 9 Hollosy F, Idei M, Csorba G, Szabo E, Bokonyi G, Seprodi A. et al . Activation of caspase-3 protease during the process of ursolic acid and its derivative-induced apoptosis.  Anticancer Res. 2001;  21 3485-91.
  • 10 Harmand P O, Duval R, Delage C, Simon A. Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu melanoma cells.  Int J Cancer. 2005;  114 1-11.
  • 11 Lauthier F, Taillet L, Trouillas P, Delage C, Simon A. Ursolic acid triggers calcium-dependent apoptosis in human Daudi cells.  Anticancer Drugs. 2000;  11 737-45.
  • 12 Choi B M, Park R, Pae H O, Yoo J C, Kim Y C, Jun C D. et al . Cyclic adenosine monophosphate inhibits ursolic acid-induced apoptosis via activation of protein kinase A in human leukaemic HL-60 cells.  Pharmacol Toxicol. 2000;  86 53-8.
  • 13 Hsu Y L, Kuo P L, Lin C C. Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells.  Life Sci. 2004;  75 303-16.
  • 14 Achiwa Y, Hasegawa K, Udagawa Y. Regulation of the phosphatidylinositol 3-kinase-Akt and the mitogen-activated protein kinase pathways by ursolic acid in human endometrial cancer cells.  Biosci Biotechnol Biochem. 2007;  71 31-7.
  • 15 Hollosy F, Meszaros G, Bokonyi G, Idei M, Seprodi A, Szende B. et al . Cytostatic, cytotoxic and protein tyrosine kinase inhibitory activity of ursolic acid in A431 human tumor cells.  Anticancer Res. 2000;  20 4563-70.
  • 16 Davis R J. Signal transduction by the JNK group of MAP kinases.  Cell. 2000;  103 239-52.
  • 17 Lin A. Activation of the JNK signaling pathway: breaking the brake on apoptosis.  Bioessays. 2003;  25 17-24.
  • 18 Mathieu J, Besancon F. Arsenic trioxide represses NF-kappaB activation and increases apoptosis in ATRA-treated APL cells.  Ann N Y Acad Sci. 2006;  1090 203-8.
  • 19 Tang G, Minemoto Y, Dibling B, Purcell N H, Li Z, Karin M. et al . Inhibition of JNK activation through NF-κB target genes.  Nature. 2001;  414 313-7.
  • 20 Kirchner D, Duyster J, Ottmann O, Schmid R M, Bergmann L, Munzert G. Mechanisms of Bcr-Abl-mediated NF-kappaB/Rel activation.  Exp Hematol. 2003;  31 504-11.
  • 21 Shishodia S, Majumdar S, Banerjee S, Aggarwal B B. Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1.  Cancer Res. 2003;  63 4375-83.
  • 22 Tamatani M, Che Y H, Matsuzaki H, Ogawa S, Okado H, Miyake S. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons.  J Biol Chem. 1999;  274 8531-8.
  • 23 Liu X S, Jiang J, Jiao X Y, Wu Y E, Lin J H. Matrine-induced apoptosis in leukemia U937 cells: involvement of caspases activation and MAPK-independent pathways.  Planta Med. 2006;  72 501-6.

Jikai Jiang

Center for Molecular Biology

School of Medicine

Shantou University

22 Xin Ling Rd

Shantou

Guangdong 515031

People’s Republic of China

Phone: +86-754-890-0203

Fax: +86-754-890-0203

Email: jkjiang@stu.edu.cn

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