Enhancement of paclitaxel-induced microtubule stabilization, mitotic arrest, and apoptosis by the microtubule-targeting agent EM012.
EM012, a semisynthetic phthalideisoquinoline alkaloid, has been recently found to target microtubules and possess anti-cancer activity. In this study, we evaluated the effects of EM012 in combination with the classic microtubule-targeting agent paclitaxel. Our results demonstrated that EM012 enhanced the anti-proliferative activity of nanomolar concentrations of paclitaxel in human breast cancer (MCF7), prostate cancer (DU145), and non-small-cell lung cancer (A549) cells. Further studies revealed that EM012 increased the ability of nanomolar concentrations of paclitaxel to induce mitotic arrest and apoptosis, without affecting microtubule polymerization. In contrast, when micromolar concentrations of paclitaxel were used, EM012 promoted paclitaxel-induced microtubule polymerization both in vitro and in cultured cells. Nevertheless, EM012 enhanced the ability of nanomolar concentrations of paclitaxel to stabilize microtubules, as indicated by increased tubulin acetylation. Our results therefore suggest a therapeutic potential of EM012/paclitaxel combination in the management of human cancer and provide mechanistic insights into the combined effects of these two microtubule-targeting agents.
Zhou
Jun
J
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. jzhou2@emory.edu
Liu
Min
M
Aneja
Ritu
R
Chandra
Ramesh
R
Joshi
Harish C
HC
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001572:Benzofurans / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; C497949:EM012 alkaloid; D007546:Isoquinolines; D017239:Paclitaxel