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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 30, 2004; DOI: 10.1124/jpet.104.078808

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Received for publication October 15, 2004.
Revised December 22, 2004.
Accepted for publication December 22, 2004.

Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells

Ya-Ling Hsu 1, Po-Lin Kuo 2, Liang-Tzung Lin 3, Chun-Ching Lin 1*

1 Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University 2 Department of Biotechnology, Chia-Nan University of Pharmacy and Science 3 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

* Address correspondence to: E-mail: aalin{at}ms24.hinet.net

Abstract

This study first investigates the anticancer effect of asiatic acid in two human breast cancer cell lines, MCF-7 and MDA-MB-231. Asiatic acid exhibited effective cell growth inhibition by inducing cancer cells to undergo S-G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased p21/WAF1 levels, and reduced amounts of cyclinB1, cyclinA, Cdc2 and Cdc25C in a p53-independent manner. Asiatic acid also reduced Cdc2 function by increasing the association of p21/WAF1/Cdc2 complex and the level of inactivated phospho-Cdc2 and phospho-Cdc25C. Asiatic acid treatment triggered the mitochondrial apoptotic pathway indicated by changing Bax/Bcl-2 ratios, cytochrome c release and caspase-9 activation, but did not act on Fas/Fas ligand pathways and the activation of caspase-8. We also found that mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2) and p38, but not c-Jun N-terminal kinase (JNK), are critical mediators in asiatic acid-induced cell growth inhibition. U0126or SB203580, specific inhibitors of MEK and p38 kinase activities, significantly decreased or delayed apoptosis. Asiatic acid was likely to confine the breast cancer cells in the S-G2/M phase mainly through the p38 pathway, because both SB203580 and p38 siRNA inhibition significantly attenuated the accumulation of inactive phospho-Cdc2 and phospho-Cdc25C proteins and the cell numbers of S-G2/M phase. Moreover, U0126 and ERK siRNA inhibition completely suppressed asiatic acid-induced Bcl-2 phosphorylation and Bax upregulation, and caspase-9 activation. Taken together, these results imply a critical role for ERK1/2 and p38 but not JNK, p53, and Fas/Fas ligand in asiatic acid-induced S-G2/M arrest and apoptosis of human breast cancer cells.


Key words: Asiatic acid, ERK1/2, apoptosis, breast cancer, cell-cycle arrest, p38




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