Comparison of effects of growth factors and protein kinase C activators on cellular sensitivity to cis-diamminedichloroplatinum(II).
The anti-proliferative activity of the DNA-interactive anti-cancer agent cis-diamminedichloroplatinum(II) (cDDP) can be modulated by intracellular signaling systems. We have investigated the effects of growth factors on the sensitivity of human cervical carcinoma (HeLa) cells to cDDP. A 24-hr pretreatment of HeLa cells with 10 ng/ml epidermal growth factor (EGF) or transforming growth factor-alpha increased the anti-proliferative activity of cDDP by 2- to 4-fold. A similar pretreatment of HeLa cells with EGF did not alter cellular sensitivity to doxorubicin or vincristine. A brief exposure (15 min) to growth factors was not sufficient for cDDP sensitization. EGF caused a modest and transient increase in cellular diacylglycerol, the endogenous activator of protein kinase C. Bryostatin I, a partial agonist of protein kinase C, antagonized phorbol ester-mediated cDDP sensitization but had no effect on EGF-mediated sensitization to cDDP. Both EGF and phorbol 12,13-dibutyrate (PDBu) enhanced the rate of [195mPt]cDDP uptake but had no effect on the rate of [195mPt]cDDP efflux in HeLa cells. Bryostatin I reversed the increase in [195mPt]cDDP content by PDBu but failed to block EGF-induced increase in [195mPt]cDDP accumulation. Therefore, although the mechanism of cDDP sensitization by both EGF and phorbol ester appears to involve enhanced drug uptake, they may utilize distinct signal transduction pathways.
Basu
A
A
Department of Pharmacology, University of Pittsburgh School of Medicine, PA 15261.
Evans
R W
RW
D054713:Bryostatins; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000032:analysis / Q000494:pharmacology*; D004075:Diglycerides / Q000032:analysis; D004317:Doxorubicin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D054713:Bryostatins; D004075:Diglycerides; D007783:Lactones; D018942:Macrolides; D016211:Transforming Growth Factor alpha; C046785:bryostatin 1; D014750:Vincristine; D004815:Epidermal Growth Factor; D004317:Doxorubicin; D011493:Protein Kinase C; D002945:Cisplatin