Benzofuran-2-acetic ester derivatives induce apoptosis in breast cancer cells by upregulating p21Cip/WAF1 gene expression in p53-independent manner.

Breast cancer is the most common malignancy and the leading cause of cancer-related death in women worldwide. High toxicity of used chemotherapeutics and resistance of cancer cells to treatments are a driving force for searching the new drug candidates for breast cancer therapy. In this study, we tested the antiproliferative effects of a series of benzofuran-2-acetic methyl ester derivatives, synthesized by a palladium-catalyzed carbonylative heterocyclization approach, on breast cancer cells. We observed that benzofuran compounds bearing a phenyl or tert-butyl substituent α to the methoxycarbonyl group significantly inhibited anchorage-dependent and -independent cell growth, and induced G0/G1 cell cycle arrest in human estrogen receptor alpha positive (MCF-7 and T47D) and in triple negative MDA-MB-231 breast cancer cells, without affecting growth of MCF-10A normal breast epithelial cells. Mechanistically, benzofuran derivatives enhanced the cyclin-dependent kinase inhibitor p21Cip/WAF1 expression at both mRNA and protein levels and this occurs transcriptionally in an Sp1-dependent manner. Moreover, benzofuran derivatives induced apoptosis, increased poly (ADP-ribose) polymerase cleavage and Bax/Bcl-2 ratio along with a marked DNA fragmentation along with a marked DNA fragmentation and a strong increase in TUNEL-positive breast cancer cells. Overall, we provide evidence that the newly tested benzofuran derivatives showed antiproliferative and pro-apoptotic activities against breast cancer cells regardless estrogen receptor status, suggesting their possible clinical development as anticancer agents.