PARP inhibitor ABT-888 affects response of MDA-MB-231 cells to doxorubicin treatment, targeting Snail expression
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Germano Mariano1, Maria Rosaria Ricciardi1, Daniela Trisciuoglio2, Michele Zampieri1,3, Fabio Ciccarone1,3, Tiziana Guastafierro1,3, Roberta Calabrese1,3, Elisabetta Valentini1, Agostino Tafuri4, Donatella Del Bufalo2, Paola Caiafa1,3, Anna Reale1
1Department of Cellular Biotechnologies and Haematology, “Sapienza” University of Rome, Italy
2Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy
3Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy
4Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, Italy
Anna Reale, e-mail: [email protected]
Keywords: PARP inhibitors, chemoresistance, Snail, breast cancer
Received: October 22, 2014 Accepted: March 23, 2015 Published: April 13, 2015
To overcome cancer cells resistance to pharmacological therapy, the development of new therapeutic approaches becomes urgent. For this purpose, the use of poly(ADP-ribose) polymerase (PARP) inhibitors in combination with other cytotoxic agents could represent an efficacious strategy. Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification that plays a well characterized role in the cellular decisions of life and death. Recent findings indicate that PARP-1 may control the expression of Snail, the master gene of epithelial-mesenchymal transition (EMT). Snail is highly represented in different resistant tumors, functioning as a factor regulating anti-apoptotic programmes. MDA-MB-231 is a Snail-expressing metastatic breast cancer cell line, which exhibits chemoresistance properties when treated with damaging agents. In this study, we show that the PARP inhibitor ABT-888 was capable to modulate the MDA-MB-231 cell response to doxorubicin, leading to an increase in the rate of apoptosis. Our further results indicate that PARP-1 controlled Snail expression at transcriptional level in cells exposed to doxorubicin. Given the increasing interest in the employment of PARP inhibitors as chemotherapeutic adjuvants, our in vitro results suggest that one of the mechanisms through which PARP inhibition can chemosensitize cancer cells in vivo, is targeting Snail expression thus promoting apoptosis.
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