title: Geldanamycin and its 17-allylamino-17-demethoxy analogue antagonize the action of Cisplatin in human colon adenocarcinoma cells: differential caspase activation as a basis for interaction.
abstract: Several chaperone-binding drugs based on geldanamycin (GA) have been synthesized, and one of them, 17-allylamino-17-demethoxygeldanamycin (17-AAG), is being developed in the clinic. Interest in the use of 17-AAG in combination with cytotoxic drugs led us to study both GA and 17-AAG with cisplatin (DDP) in the human colon adenocarcinoma cell lines HT29 and HCT116. We performed isobologram analysis of combinations of DDP with GA or 17-AAG in these cell lines using the standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to evaluate cell survival. In HCT116, the effects of GA and 17-AAG with DDP were additive and schedule dependent. In HT29 both GA and 17-AAG antagonized DDP effects resulting in cytotoxicity less than expected. We hypothesized that the antagonism in HT29 cells might be a consequence of altered p53 function in this cell line. Accordingly, we tested GA/17-AAG and DDP in combination in the HCTp5.2 cell line, which expresses a dominant-negative form of p53. In these cells too, the GA analogues antagonized DDP, suggesting a role for p53 in the observed effects. Investigation of the DDP-induced signaling pathways revealed that ansamycins block the activation of mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase pathways and c-Jun expression in HT29 cells while exerting incomplete inhibitory effects in HCT116 and HCTp5.2 cell lines. Therefore, effects on signaling are thought not to underlay the antagonism in the latter model. The ansamycins inhibited DDP-induced activation of caspases 8 and 3 in HT29 and HCTp5.2 but not in HCT116 cells, which we postulate to be the basis for higher survival of p53-deficient cells when treated with combinations of the two drugs.
authors.affiliation: University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA. vasilevs@mail.med.upenn.edu
authors.forename: Irina A
authors.initials: IA
authors.lastname: Vasilevskaya
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Rakitina
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020137:Base Pair Mismatch; D016227:Benzoquinones; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002945:Cisplatin / Q000037:antagonists & inhibitors*; D003110:Colonic Neoplasms / Q000473:pathology*; D053938:DNA Fragmentation; D004260:DNA Repair; D004789:Enzyme Activation / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D047029:Lactams, Macrocyclic; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009363:Neoplasm Proteins / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; D011809:Quinones; D016159:Tumor Suppressor Protein p53; D017828:Rifabutin; C112765:tanespimycin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin; C001277:geldanamycin