A novel biphenyl urea compound, TPD7, stimulates apoptosis through modulating Fas signaling and Bcl-2 family proteins in cervical cancer

Abstract

We recently reported that TPD7 suppressed tumor cell proliferation, and inhibited invasion, through the suppression of C-X-C chemokine receptor type 4 (CXCR4). In the present study, we investigated the anticancer effect of TPD7 on apoptosis and invasion of cervical cancer HeLa cells. Cell cycle analysis revealed that TPD7 decreased cyclin-dependent kinase (CDK)1 and cyclin D1 expression, and increased cyclin A expression, following S phase blockade. TPD7 induced chromatin condensation and significantly elevated the number of apoptotic cells, suggesting that its inhibitory effect on HeLa cells was due to the induction of cell cycle blockade and apoptosis. Mechanistically, TPD7 altered the extrinsic apoptosis pathway by upregulating Fas expression, and the intrinsic pathway by modulating Bcl-2 family proteins, p53, and NF-?B p65, leading to enhanced apoptosis. TPD7 inhibited HeLa cell invasion by downregulating the expression of matrix metallo-proteinase (MMP)-9 and CXCR4 proteins. In vivo experiments revealed that TPD7 inhibited tumor growth in HeLa cell xenografted mice. These findings indicated that TPD7 may be a potential chemoprevention agent for the management of cervical carcinoma.