Basu A, Lazo J S
Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Cancer Res. 1992 Jun 1;52(11):3119-24.
Bryostatins are an important class of protein kinase C (PKC) activators. We have investigated the effect of bryostatin 1 on the antiproliferative activity of cis-diamminedichloroplatinum(II) (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 IC50 of CP (concentration of drug required to inhibit cell proliferation by 50%) was concentration-dependent and biphasic; the maximum effect of bryostatin 1 was seen with 1 nM, but higher concentrations of bryostatin 1 (greater than or equal to 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 (greater than or equal to 10 nM) antagonized CP sensitization by phorbol esters. Bryostatin 1 was even more potent than 12-O-tetradecanoylphorbol-13-acetate in inducing PKC down-regulation, 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-[3H]DEP by 60%. The concentration- and time-dependent enhancement in CP sensitivity by bryostatin 1 was related to the increase in cis-[3H]DEP level. Thus, cellular accumulation of CP may be regulated by a PKC-dependent phosphorylation event.
苔藓抑素是一类重要的蛋白激酶C（PKC）激活剂。我们研究了苔藓抑素1对顺二氯二氨铂（II）（CP）抗增殖活性的影响。用1 nM苔藓抑素1对HeLa细胞进行24小时预处理，可使细胞对CP的敏感性提高4倍。苔藓抑素1对CP的IC50（抑制细胞增殖50%所需的药物浓度）的影响呈浓度依赖性且具有双相性；苔藓抑素1在1 nM时效果最佳，但更高浓度（大于或等于10 nM）的苔藓抑素1对CP的增敏作用较小。尽管在无细胞系统中苔藓抑素1和佛波酯对HeLa细胞PKC的刺激作用相当，但在使细胞对CP敏感方面，苔藓抑素1的效果不如佛波酯。此外，更高浓度（大于或等于10 nM）的苔藓抑素1会拮抗佛波酯对CP的增敏作用。在诱导PKC下调方面，苔藓抑素1比12 - O - 十四酰佛波醇 - 13 - 乙酸酯更有效，10 nM的苔藓抑素1可实现最大程度的下调。苔藓抑素1还增加了细胞对CP类似物顺二氯（乙二胺）铂（II）的敏感性。用1 nM苔藓抑素1进行24小时预处理可使细胞内顺式 - [3H]DEP增加60%。苔藓抑素1对CP敏感性的浓度和时间依赖性增强与顺式 - [3H]DEP水平的增加有关。因此，CP的细胞积累可能受PKC依赖性磷酸化事件的调节。
