Molecularly targeted therapy for ovarian cancer.

摘要

Ovarian cancer is the most lethal gynecological malignancy among women in the United States. One in sixty-eight women will develop ovarian cancer in their lifetime. The current first-line treatment for ovarian cancer is cisplatin. However, the tumors relap and are typically unresponsive to cisplatin treatment. Therefore, the resistance to cisplatin therapy has been a critical hurdle in the management of recurrent ovarian cancer.; The mechanisms responsible for cisplatin resistance are multifactorial that there is no single factor that can account for the resistance in every cell. In the search for new therapies to overcome/bypass cisplatin resistance, histone deacetylases (HDACs) and the PI3K/PDK-1/Akt pathway have been considered some of the most promising targets. These targets have been implicated in the tumorigenesis of many cancer types including ovarian cancers.; In the first part of this study, we assessed the anticancer effects of (S)-HDAC42, a novel HDAC inhibitor developed in our laboratory, in both cisplatin-sensitive and -resistant ovarian cancer cells in vitro, as well as in an ovarian cancer xenograft mouse model in vivo. In the second part, OSU03012, a PDK-1 inhibitor also developed in our laboratory, was evaluated in ovarian cancer cells in vitro .; Our results show that (S)-HDAC42 (i) induced apoptosis in ovarian cancer cells at low doses regardless of cisplatin sensitivity; (ii) induced cell cycle arrest at the G2/M phase with concurrent down-regulation of Cdc2 and cyclin B1 protein; (iii) stimulated cell differentiation; (iv) effectively inhibited tumor growth in CP70 tumor xenograft-bearing nude mice; and (v) enhanced the suppression of CP70 tumor growth by cisplatin in combination treatment.; The results of the second part of this project show that OSU03012 (i) effectively suppressed ovarian cancer cell growth as determined by MTT assay, irrespective of cisplatin sensitivity; (ii) caused downregulation of PDK-1/Akt signaling as indicated by the dephosphorylation of Akt and its downstream effector, p27; (iii) induced ovarian cancer cell apoptosis; (iv) stimulated cell cycle arrest at G1 or S phase; and (v) additively augmented cisplatin-mediated cytotoxicity in ovarian cancer cells.; In conclusion, these findings indicate that HDACs and PDK-1/Akt pathway play important roles in ovarian cancer survival, as the inhibition of either target greatly hinders the survival of ovarian cancers. Moreover, the novel HDAC inhibitor, (S)-HDAC42, and PDK-1 inhibitor, OSU03012, are promising anticancer agents for the treatment of ovarian cancer, either administered alone or in combination with cisplatin.