Benzofuran-2-acetic Ester Derivatives Induce Apoptosis in Breast Cancer Cells by Upregulating p21Cip/WAF1 Gene Expression in p53-Independent Manner

Publication date: Available online 15 January 2017
Source:DNA Repair
Author(s): Cinzia Giordano, Daniela Rovito, Ines Barone, Raffaella Mancuso, Daniela Bonofiglio, Francesca Giordano, Stefania Catalano, Bartolo Gabriele, Sebastiano Andò
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 p21^Cip/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.



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