title: Benzofuran-2-acetic ester derivatives induce apoptosis in breast cancer cells by upregulating p21Cip/WAF1gene expression in p53-independent manner.
abstract: 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/WAF1expression 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.
authors.affiliation: Centro Sanitario,University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Centro Sanitario,University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rovito
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.affiliation: Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical Technologies, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mancuso
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giordano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy. Electronic address: stefcatalano@libero.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.affiliation: Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical Technologies, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Bartolo
authors.initials: B
authors.lastname: Gabriele
authors.affiliation: Centro Sanitario,University of Calabria, Arcavacata di Rende, CS, Italy; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy. Electronic address: sebastiano.ando@unical.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects* / Q000235:genetics; D004952:Esters / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006868:Hydrolysis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004952:Esters; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases
keywords: Anticancer activity; Benzofurans; Breast cancer; p21Cip/WAF1