Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, California 92697, USA. lifangxatuci.edu
Melanoma Res. 2013 Apr;23(2):102-13. doi: 10.1097/CMR.0b013e32835df5e4.
Treatment of metastatic melanoma has long been a challenge because of its resistance to traditional chemotherapeutics, leading to the search for alternative strategies. Aurora kinases are key mitotic regulators that are frequently overexpressed in various cancers including melanoma, making them ideal targets for drug development. Several Aurora kinase inhibitors have been developed and tested preclinically and clinically. PHA-739358 is currently one of the most advanced clinical compounds being tested in phase II clinical trials; however, its antitumor effect has not been tested in melanoma. In this study, the antiproliferative and anti-invasive effects of PHA-739358 were investigated in melanoma cell lines. The results demonstrated that PHA-739358 produces a time-dependent and dose-dependent inhibition of cell proliferation, induction of apoptosis, and inhibition of cell migration. Downregulation of matrix metalloproteinase-2 by the inhibition of NFκB-signaling pathway may contribute to PHA-739358-induced inhibition of migration. Furthermore, PHA-739358 enhanced temozolomide and Plx4032-induced apoptosis. This study suggests that Aurora kinase inhibitors may provide a new strategy for the treatment of advanced melanoma.
治疗转移性黑色素瘤一直是一个挑战，因为它对传统的化疗药物有耐药性，这导致人们寻求替代策略。极光激酶是关键的有丝分裂调节剂，在包括黑色素瘤在内的各种癌症中经常过表达，使它们成为药物开发的理想靶点。已经开发并在临床前和临床中测试了几种极光激酶抑制剂。PHA-739358 是目前正在进行 II 期临床试验的最先进的临床化合物之一；然而，它在黑色素瘤中的抗肿瘤作用尚未得到测试。在这项研究中，研究了 PHA-739358 在黑色素瘤细胞系中的抗增殖和抗侵袭作用。结果表明，PHA-739358 产生时间依赖性和剂量依赖性的细胞增殖抑制、诱导细胞凋亡和抑制细胞迁移。NFκB 信号通路的抑制导致基质金属蛋白酶-2 的下调可能有助于 PHA-739358 诱导的迁移抑制。此外，PHA-739358 增强了替莫唑胺和 Plx4032 诱导的细胞凋亡。这项研究表明，极光激酶抑制剂可能为治疗晚期黑色素瘤提供新的策略。
