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Comparison of effects of growth factors and protein kinase C activators on cellular sensitivity to cis ‐diamminedichloroplatinum(II)
Author(s) -
Basu Alakananda,
Evans Rhobert W.
Publication year - 1994
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910580423
Subject(s) - protein kinase c , epidermal growth factor , hela , sensitization , diacylglycerol kinase , kinase , activator (genetics) , signal transduction , growth factor , protein kinase a , biology , microbiology and biotechnology , chemistry , biochemistry , cell , immunology , receptor
The anti‐proliferative activity of the DNA‐interactive anti‐cancer agent cis ‐diamminedichloroplatinum(11) (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‐α increased the anti‐proliferatfve 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 cODP. Both EGF and phorbol 12,13‐dibutyrate (PDBu) enhanced the rate of [ 195m Pt]cDDP uptake but had no effect on the rate of [ 195m Pt]cDDP efflux in HeLa cells. Bryostatin I reversed the increase in [ 195m Pt]cDDP content by PDBu but failed to block EGF‐induced increase in [ 195m Pt]cDDP accumulation. Therefore, although the mechanism of tDDP sensitization by both EGF and phorbol ester appears to involve enhanced drug uptake, they may utilize distinct signal transduction pathways.