Enhancement of sensitivity to platinum(II)-containing drugs by 12-O-tetradecanoyl-phorbol-13-acetate in a human ovarian carcinoma cell line

Abstract

Sensitivity to platinum-containing drugs is believed to be a function of how much drug enters the cell, the extent of DNA adduct formation and the rate at which DNA is repaired. Activation of protein kinase C by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was found to enhance the sensitivity of human ovarian carcinoma 2008 cells to cisplatin (DDP), carboplatin (CBDCA) and (glycolato-O,O') diammineplatinum(II) (254-S). TPA was able to enhance the sensitivity of the DDP-resistant 2008/C13*5.25 subline to each of the three drugs to the same extent as for the 2008 cells. TPA produced no significant change in the uptake of [3H]cis-dichloro(ethylenediamine)-platinum(II). ([3H]DEP) or CBDCA. It did not alter glutathione content or glutathione-S-transferase activity, and induced rather than suppressed metallothionein IIA mRNA levels. TPA did increase the formation of intrastrand guanine-guanine cross-links by a factor of 1.5 +/- 0.3 (s.d.), and reduced the fraction of intrastrand adducts removed from DNA over the subsequent 24 h by a factor of 1.3 +/- 0.2 (s.d.) (n = 4; P < 0.05), however, these effects were too small to account for the degree of TPA-induced sensitisation. These results indicate that the mechanism of TPA-induced sensitisation is not specific to any one structural form of platinum-containing drug, and that it is not readily explicable on the basis of an effect on the four major parameters currently believed to regulate DDP sensitivity.