Scala S, Dickstein B, Regis J, Szallasi Z, Blumberg P M, Bates S E
Medicine Branch, Clinical Oncology Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 1995 Dec;1(12):1581-7.
The function of P-glycoprotein (Pgp), which confers multidrug resistance by active efflux of drug, is thought to be dependent on phosphorylation. Previous studies have suggested that protein kinase C (PKC) plays an important role in Pgp phosphorylation. We report here the effects of bryostatin 1, a unique PKC activator and inhibitor, on Pgp function in a multidrug-resistant MCF-7 human breast cancer subline which overexpresses PKC-alpha. Bryostatin 1 (100 nM) decreased Pgp phosphorylation after 24 h of treatment. In contrast, it did not affect Pgp function as demonstrated by the accumulation of [3H]vinblastine and rhodamine 123. We compared the effect of bryostatin 1 treatment on PKC-alpha with that of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (200 nM). 12-O-tetradecanoylphorbol-13-acetate caused translocation of PKC-alpha from the cytosol to the cell membrane after a 10-min treatment and its down-regulation after 24 h of treatment. Likewise, bryostatin 1 (100 nM) caused translocation, but only after longer treatment (1 h), and it caused down-regulation of PKC-alpha at 24 h of treatment. Thus, while the MCF-7TH cells overexpress the PKC-alpha isoform, and its down-regulation by bryostatin 1 is associated with decreased Pgp phosphorylation, these alterations do not modulate drug transport. We conclude that, while bryostatin 1 may be useful clinically because of its ability to inhibit PKC, it is not able to reverse Pgp-mediated multidrug resistance.
P-糖蛋白（Pgp）通过药物的主动外排赋予多药耐药性，其功能被认为依赖于磷酸化。先前的研究表明蛋白激酶C（PKC）在Pgp磷酸化中起重要作用。我们在此报告了苔藓抑素1（一种独特的PKC激活剂和抑制剂）对过表达PKC-α的多药耐药性MCF-7人乳腺癌亚系中Pgp功能的影响。苔藓抑素1（100 nM）处理24小时后可降低Pgp磷酸化。相比之下，如[3H]长春碱和罗丹明123的蓄积所示，它不影响Pgp功能。我们比较了苔藓抑素1处理对PKC-α的影响与佛波酯12-O-十四酰佛波醇-13-乙酸酯（200 nM）的影响。12-O-十四酰佛波醇-13-乙酸酯处理10分钟后导致PKC-α从细胞质转位到细胞膜，处理24小时后导致其下调。同样，苔藓抑素1（100 nM）也导致转位，但仅在更长时间处理（1小时）后出现，并且在处理24小时时导致PKC-α下调。因此，虽然MCF-7TH细胞过表达PKC-α同工型，且苔藓抑素1对其下调与Pgp磷酸化降低相关，但这些改变并未调节药物转运。我们得出结论，虽然苔藓抑素1因其抑制PKC的能力在临床上可能有用，但它不能逆转Pgp介导的多药耐药性。
