title: Overcoming CPT-11 resistance by using a biscoclaurine alkaloid, cepharanthine, to modulate plasma trans-membrane potential.
abstract: Irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin, (CPT-11) resistance was overcome by using a biscoclaurine alkaloid, cepharanthine, in CPT-11- and multidrug-resistant 50MT-1 cells. 50MT-1 cells were established from a mouse breast-cancer cell line, FM3A, by subjecting the cells to a low dose of CPT-11 continuously. 50MT-1 cells exhibited resistance to CPT-11 (40-fold in colony-formation assay) and to other drugs such as doxorubicin (11.7-fold) and etoposide (VP-16) (16.8-fold). The plasma trans-membrane potential was lower in 50MT-1 cells than in FM3A cells, although there were no differences in expressions of P-glycoprotein and of DNA topoisomerase-I and -II proteins. The lower membrane potential in 50MT-1 cells was augmented by co-treatment with a non-toxic dose of cepharanthine. CPT-11 resistance in 50MT-1 cells was overcome (5.0- to 1.4-fold, 6-hr exposure) by the co-treatment with cepharanthine through increasing intracellular accumulation of CPT-11. Resistance to doxorubicin and VP-16 was also overcome by cepharanthine treatment (2.5- to 0.69-fold and 4.2- to 1.4-fold respectively). We conclude that the modification of plasma trans-membrane potential by cepharanthine should be effective in overcoming CPT-11 and multidrug resistance in 50MT-1 cells.
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Minami-ku, Hiroshima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Aogi
authors.forename: M
authors.initials: M
authors.lastname: Nishiyama
authors.forename: R
authors.initials: R
authors.lastname: Kim
authors.forename: N
authors.initials: N
authors.lastname: Hirabayashi
authors.forename: T
authors.initials: T
authors.lastname: Toge
authors.forename: A
authors.initials: A
authors.lastname: Mizutani
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: H
authors.initials: H
authors.lastname: Sumiyoshi
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: M
authors.initials: M
authors.lastname: Yamakido
authors.forename: T
authors.initials: T
authors.lastname: Kusano
authors.forename: T
authors.initials: T
authors.lastname: Andoh
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D044182:Benzylisoquinolines; D001692:Biological Transport / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002462:Cell Membrane / Q000378:metabolism; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D000077146:Irinotecan; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014407:Tumor Cells, Cultured; D052117:Benzodioxoles
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D002166:Camptothecin; D000077146:Irinotecan; C006947:cepharanthine; D052117:Benzodioxoles