Sledge George W, Gökmen-Polar Yesim
Departments of Medicine and Pathology, Indiana University Cancer Center, Indianapolis, IN 46220, USA.
Semin Oncol. 2006 Jun;33(3 Suppl 9):S15-8. doi: 10.1053/j.seminoncol.2006.03.019.
Combining existing breast cancer therapies with novel agents that interfere with major signaling pathways is a promising approach. Targeting protein kinase C (PKC)-beta may serve as an attractive candidate in this regard for the following reasons: first, PKC-beta II (a splice variant of PKC-beta) has been implicated in tumorigenesis in human and rodent models. Second, PKC-beta, mainly PKC-betaII, is the predominant mediator of vascular endothelial growth factor-induced endothelial cell proliferation, which is a well-known stimulator of tumor angiogenesis and growth in breast cancer. There is increasing evidence that PKC-beta-selective inhibitors are effective in both preclinical and clinical trials. Enzastaurin, a potent inhibitor of PKC-beta, suppresses both tumor growth and tumor-induced angiogenesis in human tumor xenografts. Phase II trials of enzastaurin in recurrent high-grade gliomas and lymphomas have shown promising results. A similar compound, ruboxistaurin, is also under investigation in clinical trials for diabetic complications. This review focuses on the rationale for using PKC-beta as a therapeutic target at both the preclinical and clinical levels in breast cancer.
将现有的乳腺癌治疗方法与干扰主要信号通路的新型药物相结合是一种很有前景的方法。靶向蛋白激酶C（PKC）-β在这方面可能是一个有吸引力的候选靶点，原因如下：第一，PKC-βII（PKC-β的一种剪接变体）在人类和啮齿动物模型的肿瘤发生中起作用。第二，PKC-β，主要是PKC-βII，是血管内皮生长因子诱导的内皮细胞增殖的主要介质，而血管内皮生长因子是乳腺癌中肿瘤血管生成和生长的众所周知的刺激因子。越来越多的证据表明，PKC-β选择性抑制剂在临床前和临床试验中均有效。恩杂鲁胺，一种有效的PKC-β抑制剂，可抑制人肿瘤异种移植模型中的肿瘤生长和肿瘤诱导的血管生成。恩杂鲁胺在复发性高级别胶质瘤和淋巴瘤中的II期试验已显示出有希望的结果。一种类似的化合物，鲁索替尼，也正在进行糖尿病并发症的临床试验研究。本综述重点关注在乳腺癌的临床前和临床水平上使用PKC-β作为治疗靶点的理论依据。
