In vitro interaction of liposomal valinomycin and platinum analogs: cytotoxic and cytokinetic effects.
Cisplatin is the most active agent in the chemotherapy of ovarian cancer and this activity can be enhanced by liposomal valinomycin (MLV-VM) in vitro. To test whether MLV-VM is capable of augmenting the cytotoxic and cytokinetic effects of other platinum analogs, drug combinations of MLV-VM and platinum drugs were tested against two human ovarian cancer cell lines (OVCAR-3 and CaOV-3) and on Chinese hamster ovary (CHO) cells in vitro. MLV-VM enhanced the sensitivity to cisplatin, ormaplatin and carboplatin on human ovarian carcinoma cells that show various degrees of drug sensitivity. This interaction was shown to be truly synergistic by median-effect analysis up to 90% cell kill. The combination index at 50% cell kill (Cl50) was also used to quantitate the extent of drug synergy. In the OVCAR-3 cell line, for example, the Cl50s were 0.62, 0.85 and 0.8 for cisplatin, ormaplatin and carboplatin, respectively. DNA histograms obtained by flow cytometry showed that CHO cells treated with cisplatin alone accumulated in the S-G2 segment, with a partial G2 block. The addition of 2 microM VM with cisplatin, significantly enhanced the accumulation of cells at the G2/M phase. Our results further demonstrate that in vitro treatment with VM, cisplatin and/or combination is associated with an increase in protein kinase C (PKC) activity. These findings suggest that accumulation of cells at G2/M phases and modulation of PKC activity could be among the basis for the cytotoxic synergism observed between cisplatin and VM.
Department of Pharmacology, University of North Carolina at Chapel Hill 27599-7365.
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Sakata
D000818:Animals; D016466:CHO Cells / Q000166:cytology / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D006224:Cricetinae; D004337:Drug Carriers; D004357:Drug Synergism; D004789:Enzyme Activation; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008081:Liposomes; D008938:Mitosis / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D014634:Valinomycin / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity
D004337:Drug Carriers; D008081:Liposomes; D009944:Organoplatinum Compounds; D014634:Valinomycin; D011493:Protein Kinase C