Carcinogenesis Advance Access published online on February 10, 2005
Carcinogenesis, doi:10.1093/carcin/bgi041
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1 Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 100, Taiwan
* To whom correspondence should be addressed. Drug resistance is one of the main obstacles to successful cancer treatment. The availability of agents that are highly effective against drug-resistant cancer cells is therefore essential. The present study was performed to examine the anticancer effects of evodiamine, a major constituent of the Chinese herb Evodiae Fructus, in adriamycin-resistant human breast cancer NCI/ADR-RES cells. Evodiamine inhibited proliferation of NCI/ADR-RES cells in a concentration-dependent manner with a GI50 of 0.59 ±0.11 µM. At 1 µM this agent also caused substantial apoptosis. FACScan flow cytometric analysis of cell cycle progression revealed that a G2/M arrest was initiated after 12-h exposure to the drug. Evodiamine increased tubulin polymerization as determined by immunocytochemical and in vivo tubulin polymerization analyses. In a time- and concentration-dependent manner, evodiamine also promoted the phosphorylations of Raf-1 kinase and of Bcl-2. The phosphorylation site of Raf-1 kinase was identified to be serine 338. The in vivo anticancer effects of evodiamine were evaluated in Balb-c/nude mice following tumor xenograft implantation of NCI/ADR-RES cells. The antitumor activity of evodiamine against the human multiple-drug resistant tumor xenograft was found to be superior to that of paclitaxel. Evodiamine therefore represents a highly promising chemotherapeutic agent for treatment of human multiple-drug resistant cancer cells.
Received September 17, 2004
Revised January 30, 2005
Accepted February 1, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Antitumor mechanism of evodiamine, a constituent from Chinese herb Evodiae Fructus, in human multiple-drug resistant breast cancer NCI/ADR-RES cells in vitro and in vivo
2 School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Che-Ming Teng, E-mail: cmteng{at}ntumc.org
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