A novel PI3K inhibitor displays potent preclinical activity against an androgen-independent and PTEN-deficient prostate cancer model established from the cell line PC3

作者：Shi, Min; Zhou, Xiumin; Zhang, Zubin; Wang, Man; Chen, Guodong; Han, Kunkun; Cao, Biyin; Liu, Zhaopeng; Mao, Xinliang^*

来源：Toxicology Letters, 2014, 228(3): 133-139.

DOI：10.1016/j.toxlet.2014.05.003

• Prostate cancer
• PI3K/AKT
• PTEN
• Androgen-independence
• BENC-511

Recent studies demonstrated that targeting the phosphatidylinositide 3-kinase (PI3K)/AKT signaling pathway is a major strategy for the treatment of androgen-independent prostate cancer. In the present study, we developed an analog BENC-511 from a recently reported PI3K inhibitor S14161 by structural optimization. Using PC3 and DU145 as the model cell lines, we found PTEN-deficient PC3 cells were more sensitive than PTEN-expressing DU145 ones in terms of cell proliferation, apoptosis, and caspase-3 activation. These findings were consistent with the inhibition on PI3K/AKT signals. BENC-511 preferably suppressed ART activation in PC3 over DU145 cells. Notably, PTEN restoration attenuated BENC-511 induced apoptosis. Moreover, BENC-511 displayed great therapeutic efficacy in a PC3-derived prostate cancer model in nude mice. With an oral dosage of 50 mg/kg, BENC-511 decreased tumor growth more than 50% in 27 days, which was accompanied with PARP cleavage, but did not show overt toxicity. This study lays a solid rationale for the development of BENC-511 as a drug for the treatment of PTEN-deficient and androgen-independent prostate cancers.

• 出版日期2014-8-4
• 单位山东大学; 苏州大学