title: Cytotoxic activity of Apomine is due to a novel membrane-mediated cytolytic mechanism independent of apoptosis in the A375 human melanoma cell line.
abstract: Apomine, a novel bisphosphonate ester, has demonstrated anticancer activity in a variety of cancer cell lines; however, its mechanism of cytotoxicity is not well understood. Previous work has demonstrated that Apomine induces cell death by activation of caspase-3 in several cancer cell types. However, we have demonstrated that Apomine induces cell death in the A375 human melanoma cell line through a novel membrane-mediated mechanism that is independent of caspase-3 activation. This mechanism of membrane lysis may apply to other bisphosphonates and may be an important mechanism for overcoming resistance to apoptosis. Interestingly, Apomine-mediated cell death in the A375 and UACC 3093 human melanoma cell lines is also independent of N-Ras farnesylation, which was a previously described mechanism of action for Apomine in other cancer cell types. These data suggest that Apomine induces cell death through a novel plasma membrane-mediated cytolytic pathway, independent of caspase-3 activation and N-Ras farnesylation.
authors.affiliation: Arizona Cancer Center, The University of Arizona, 1515 N, Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Pourpak
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dorr
authors.forename: Ross O
authors.initials: RO
authors.lastname: Meyers
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Powell
authors.forename: Steven P
authors.initials: SP
authors.lastname: Stratton
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004164:Diphosphonates / Q000633:toxicity*; D004789:Enzyme Activation / Q000502:physiology; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D018631:ras Proteins / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004164:Diphosphonates; C407151:apomine; D007770:L-Lactate Dehydrogenase; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D018631:ras Proteins; D013936:Thymidine