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.
Drug resistance is one of the main obstacles to the successful treatment of cancer. 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 the proliferation of NCI/ADR-RES cells in a concentration-dependent manner with a GI50 of 0.59 +/- 0.11 microM. This agent also caused a substantial apoptosis at 1 microM. FACScan flow cytometric analysis of cell cycle progression revealed that a G2/M arrest was initiated after a 12-h exposure to the drug. Evodiamine increased tubulin polymerization as determined by the immunocytochemical and in vivo tubulin polymerization analyses. In a time- and concentration-dependent manner, evodiamine also promoted the phosphorylations of Raf-1 kinase and Bcl-2. The phosphorylation site of Raf-1 kinase was identified to be serine338. The in vivo anticancer effects of evodiamine were evaluated in Balb-c/nude mice following a 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 in the treatment of human multiple-drug resistant cancer cells.
Liao
Cho-Hwa
CH
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Pan
Shiow-Lin
SL
Guh
Jih-Hwa
JH
Chang
Ya-Ling
YL
Pai
Hui-Chen
HC
Lin
Chun-Hung
CH
Teng
Che-Ming
CM
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D032086:Evodia / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects; D017239:Paclitaxel / Q000493:pharmacokinetics; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; C406544:Gosyuyu; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D011804:Quinolines; C049639:evodiamine; D019908:Proto-Oncogene Proteins c-raf; D017239:Paclitaxel