title: 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.
abstract: 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.
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Cho-Hwa
authors.initials: CH
authors.lastname: Liao
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chang
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Pai
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Lin
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
mesh_terms: 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
chemical_list: 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