Comparison of effects of growth factors and protein kinase C activators on cellular sensitivity to cis-diamminedichloroplatinum(II)

Int J Cancer. 1994 Aug 15;58(4):587-91. doi: 10.1002/ijc.2910580423.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Bryostatins
  • Cell Division / drug effects
  • Cell Survival
  • Cisplatin / analysis
  • Cisplatin / pharmacology*
  • Diglycerides / analysis
  • Doxorubicin / pharmacology
  • Epidermal Growth Factor / pharmacology*
  • HeLa Cells
  • Humans
  • Lactones / pharmacology
  • Macrolides
  • Protein Kinase C / antagonists & inhibitors*
  • Transforming Growth Factor alpha / pharmacology*
  • Vincristine / pharmacology

Substances

  • Bryostatins
  • Diglycerides
  • Lactones
  • Macrolides
  • Transforming Growth Factor alpha
  • bryostatin 1
  • Vincristine
  • Epidermal Growth Factor
  • Doxorubicin
  • Protein Kinase C
  • Cisplatin