cis-Diamminedichloroplatinum(II) resistant human tumor cell lines are collaterally sensitive to PtCl4(Rh-123)2: evidence for mitochondrial involvement.
Three human tumor cell lines made resistant to cis-diamminedichloroplatinum(II) (CDDP), SCC-25/CP, MCF-7/CP, and C13, are more sensitive to rhodamine-123 [tetrachloroplatinum(II)] [(PtCl4(Rh-123)2] than are the corresponding parental cell lines. The CDDP-resistant cells have higher intracellular concentrations of PtCl4(Rh-123)2 for the same exposure than do the parent cells. Each of the CDDP-resistant cell lines has an increased level of cytochrome c oxidase activity compared with the parent cell lines, indicating that the resistant cells have greater mitochondrial mass or activity than the parent cells. In fact, there was a linear correlation between the increase in cytochrome c oxidase activity and the increased sensitivity to PtCl4(Rh-123)2 in the CDDP-resistant lines. Exposure of the cells to each of the mitochondrial effectors, chloramphenicol, FCCP, oligomycin, or antimycin prior to and during exposure to CDDP or PtCl4(Rh-123)2 had variable effects on the cytotoxicity of the platinum complexes in the parental lines. However, there was a consistent decrease in the cytotoxicity of PtCl4(Rh-123)2 in the CDDP-resistant cells in the presence of the mitochondrial effectors such that, in some cases, the CDDP-resistant lines were now less responsive to PtCl4(Rh-123)2 than were the parent cell lines. These studies indicate that mitochondrial alterations may be an important component of CDDP resistance in these cell lines and that PtCl4(Rh-123)2 may represent a prototype platinum complex useful in the treatment of CDDP resistant tumors.
Ara
G
G
Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Kusumoto
T
T
Korbut
T T
TT
Cullere-Luengo
F
F
Teicher
B A
BA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012235:Rhodamines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D012235:Rhodamines; C050316:tetrachloroplatinate dianion-rhodamine-123 complex; D002945:Cisplatin