The pan-Aurora kinase inhibitor, PHA-739358, induces apoptosis and inhibits migration in melanoma cell lines.
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.
Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, California 92697, USA. lifangxatuci.edu
Lifang
L
Xie
Frank L
FL
Meyskens
D017209:Apoptosis / Q000187:drug effects*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology*; D018929:Cell Culture Techniques; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D014162:Transfection
D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D064127:Aurora Kinases; C523797:danusertib