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

Alakananda Basu, Rhobert W. Evans

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17 Citations (Scopus)

Abstract

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 [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 tDDP sensitization by both EGF and phorbol ester appears to involve enhanced drug uptake, they may utilize distinct signal transduction pathways.

Original languageEnglish
Pages (from-to)587-591
Number of pages5
JournalInternational Journal of Cancer
Volume58
Issue number4
DOIs
StatePublished - 15 Aug 1994

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Epidermal Growth Factor
Protein Kinase C
Intercellular Signaling Peptides and Proteins
HeLa Cells
Bryostatins
Diglycerides
Transforming Growth Factors
Vincristine
Phorbol Esters
Antineoplastic Agents
Doxorubicin
Signal Transduction
Carcinoma
Pharmaceutical Preparations
phorbol

Cite this

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title = "Comparison of effects of growth factors and protein kinase C activators on cellular sensitivity to cis‐diamminedichloroplatinum(II)",
abstract = "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 [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 tDDP sensitization by both EGF and phorbol ester appears to involve enhanced drug uptake, they may utilize distinct signal transduction pathways.",
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N2 - 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 [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 tDDP sensitization by both EGF and phorbol ester appears to involve enhanced drug uptake, they may utilize distinct signal transduction pathways.

AB - 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 [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 tDDP sensitization by both EGF and phorbol ester appears to involve enhanced drug uptake, they may utilize distinct signal transduction pathways.

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