Sensitization of Human Cervical Carcinoma Cells to cis-Diamminedichloroplatinum(II) by Bryostatin l

Alakananda Basu, John S. Lazo

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Abstract

Bryostatins are an important class of protein kinase C (PKQ activa-tors. We have investigated the effect of bryostatin 1 on the antiprolifer-ative activity of cis-diamminedichloroplatinum(ll) (CP). A 24-h pretreatment of HeLa cells with 1 nM bryostatin 1 increased cellular sensitivity to CP by 4-fold. The effect of bryostatin 1 on the IQo of CP (concentration of drug required to inhibit cell proliferation by 50%) was concentration-dependent and triphasic; the maximum effect of bryostatin 1 was seen with 1 nM, but higher concentrations of bryostatin 1 (>10 nM) produced less CP sensitization. Although bryostatin 1 and phorbol esters caused an equivalent stimulation of HeLa cell PKC in cell-free systems, bryostatin 1 was less effective than phorbol esters in sensitizing cells to CP. Additionally, higher concentrations of bryostatin 1 (>10 nM) antagonized CP sensitization by phorbol esters. Bryostatin 1 was even more potent than 12-O-tetradecanoylphorbol-13-acetate in inducing PKC down-regu-lation, and the maximum down-regulation was achieved with 10 nM bryostatin 1. Bryostatin 1 also increased cellular sensitivity to a CP analogue, cis-dichloro(ethylenediamine)platinum(II). A 24-h pretreatment with 1 nM bryostatin 1 increased cellular cis-pHJDEP by 60%. The concentration- and time-dependent enhancement in CP sensitivity by bryostatin 1 was related to the increase in cis-pHJDEP level. Thus, cellular accumulation of CP may be regulated by a PKC-dependent phosphorylation event.

Original languageEnglish
Pages (from-to)3119-3124
Number of pages6
JournalCancer Research
Volume52
Issue number11
Publication statusPublished - 1 Jan 1992

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