Dan Shingo, Yoshimi Hisashi, Okamura Mutsumi, Mukai Yumiko, Yamori Takao
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Biochem Biophys Res Commun. 2009 Jan 30;379(1):104-9. doi: 10.1016/j.bbrc.2008.12.015. Epub 2008 Dec 16.
Phosphoinositide 3-kinase (PI3K) is a potential target in cancer therapy. Inhibition of PI3K is believed to induce apoptosis. We recently developed a novel PI3K inhibitor ZSTK474 with antitumor efficacy. In this study, we have examined the underlying mode of action by which ZSTK474 exerts its antitumor efficacy. In vivo, ZSTK474 effectively inhibited the growth of human cancer xenografts. In parallel, ZSTK474 treatment suppressed the expression of phospho-Akt, suggesting effective PI3K inhibition, and also suppressed the expression of nuclear cyclin D1 and Ki67, both of which are hallmarks of proliferation. However, ZSTK474 treatment did not increase TUNEL-positive apoptotic cells. In vitro, ZSTK474 induced marked G(0)/G(1) arrest, but did not increase the subdiploid cells or activate caspase, both of which are hallmarks of apoptosis. These results clearly indicated that inhibition of PI3K by ZSTK474 did not induce apoptosis but rather induced strong G(0)/G(1) arrest, which might cause its efficacy in tumor cells.
磷酸肌醇3激酶（PI3K）是癌症治疗中的一个潜在靶点。抑制PI3K被认为可诱导细胞凋亡。我们最近开发了一种具有抗肿瘤功效的新型PI3K抑制剂ZSTK474。在本研究中，我们探究了ZSTK474发挥其抗肿瘤功效的潜在作用模式。在体内，ZSTK474有效抑制了人癌异种移植瘤的生长。同时，ZSTK474处理抑制了磷酸化Akt的表达，提示PI3K被有效抑制，并且还抑制了核周期蛋白D1和Ki67的表达，这两者都是增殖的标志。然而，ZSTK474处理并未增加TUNEL阳性凋亡细胞。在体外，ZSTK474诱导明显的G(0)/G(1)期阻滞，但未增加亚二倍体细胞数量或激活半胱天冬酶，这两者都是细胞凋亡的标志。这些结果清楚地表明，ZSTK474抑制PI3K并未诱导细胞凋亡，而是诱导了强烈的G(0)/G(1)期阻滞，这可能是其在肿瘤细胞中发挥功效的原因。
