title: EM012, a microtubule-interfering agent, inhibits the progression of multidrug-resistant human ovarian cancer both in cultured cells and in athymic nude mice.
abstract: Drug resistance, in particular multidrug resistance, is a serious problem that impedes the effectiveness of chemotherapy. Multidrug resistance results mainly from an enhanced efflux of drugs by drug pumps located on the cell membrane such as P-glycoprotein. In the study reported here we showed that EM012, a microtubule-interfering agent, is a weak substrate for P-glycoprotein and inhibited the proliferation of A2780/ADR human ovarian cancer cells, which possess multidrug resistance due to P-glycoprotein overexpression. A2780/ADR cells treated with EM012 exhibited pronounced mitotic arrest, developed large multilobed nuclei, and eventually died through the initiation of apoptosis. Intraperitoneal treatment of A2780/ADR xenograft tumors in athymic nude mice with EM012 significantly inhibited tumor progression through triggering apoptosis and conferred an apparent survival advantage. Furthermore, EM012 treatment did not cause detectable toxicity to normal tissues. These findings suggest that EM012 may serve as a novel chemotherapeutic agent for the treatment of multidrug-resistant human ovarian cancer.
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Roopa
authors.initials: R
authors.lastname: Luthra
authors.forename: Jeremy
authors.initials: J
authors.lastname: Jones
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chandra
authors.forename: Rajeshwar R
authors.initials: RR
authors.lastname: Tekmal
authors.forename: Harish C
authors.initials: HC
authors.lastname: Joshi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007546:Isoquinolines / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D001572:Benzofurans; C497949:EM012 alkaloid; D007546:Isoquinolines