Protein kinase C inhibitor Gö6976 augments caffeine-induced reversal of chemoresistance to cis-diamminedichloroplatinum-II (CDDP) in a human ovarian cancer model.
OBJECTIVE
Novel strategies for the treatment of chemoresistant ovarian cancer are needed. Caffeine and related compounds have been shown to over-ride G2/M arrest in ovarian cancer cells, increasing toxicity to chemotherapy. Newer compounds have been developed which may have the same effect as and exhibit synergism with caffeine, allowing the use of lower doses.


METHODS
We investigated the effects of caffeine and Gö6976 in the presence of CDDP in the SKOV3 and A2780 cell lines using proliferation, cell-cycle analysis, apoptosis, and AKT expression.


RESULTS
Proliferation of cancer cells was decreased in a dose-dependent manner with caffeine and CDDP, but doses of caffeine required for significant inhibition were higher than that achievable in patients. Gö6976, a global PKC inhibitor with G2/M over-ride capability similar to caffeine, when combined with caffeine and CDDP at doses below that required for cell-cycle over-ride produced the growth inhibitory effects of a ten-fold higher caffeine concentration in both cell lines. CDDP induced G2/M arrest was significantly abrogated by caffeine but not by Gö6976 alone and no additional effect was seen on G2/M over-ride by the addition of Gö6976 to caffeine. Addition of Gö6976 to caffeine and CDDP did increase apoptosis but without altering phospho-AKT.


CONCLUSIONS
Gö6976, when added to caffeine at doses below that required for cell-cycle over-ride, augments caffeine in overcoming CDDP resistance in this experimental system. G2/M over-ride is not the mechanism underlying the inhibition of proliferation. An AKT-independent apoptotic mechanism may be responsible.
Qamar
Lubna
L
Department of Obstetrics and Gynecology, Division of Basic Reproductive Sciences and Gynecologic Oncology, University of Colorado Denver Health Sciences Center, Denver, CO 80262, USA.
Davis
Ryan
R
Anwar
Adil
A
Behbakht
Kian
K
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*
D002227:Carbazoles; C081021:Go 6976; D002110:Caffeine; D011493:Protein Kinase C; D002945:Cisplatin