PBOX-15 induces apoptosis and improves the efficacy of oxaliplatin in human colorectal cancer cell lines.

Abstract

An emerging new class of targeted therapeutic molecules against the enzyme fatty acid amide hydrolase (FAAH) is a novel series of pyrrolo-1,5-benzoxa(thia)zepine compounds. A member of this family, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), is a tubulin depolymerizing agent displaying a proapoptotic activity in a variety of human tumor cell types, including those derived from both solid and hematological malignancies, with minimal toxicity towards normal blood and bone marrow cells. In this study, we evaluated the PBOX-15-mediated effects in human colorectal cancer cell (CRC) lines. The compound, used at doses equal to or greater than 1 μM inhibits the proliferation of human CRC cell lines in a dose- and time-dependent manner, inducing a significant cell cycle arrest in the G2/M phase. DNA fragmentation assays and western blot analysis demonstrated that treatments prolonged over 48 h triggered a strong activation of the intrinsic apoptotic pathway as indicated by activation of caspase-3, caspase-9 and PARP. Moreover, nanomolar doses of PBOX-15, unable to cause microtubule depolymerization, significantly improved the oxaliplatin and 5-fluouracil-induced anti-proliferative effects in CRC cell lines. These results showed, for the first time, that PBOX-15 represents a promising compound for the treatment of human CRC and a strong candidate for novel therapeutic options.

• Authors: Giuseppina Gangemi, Patrizia Gazzerro, Donatella Fiore, Maria Chiara Proto, Stefania Butini, Sandra Gemma, Alice Casagni, Chiara Laezza, Mario Vitale, Alessia Ligresti, Vincenzo Di Marzo, Daniela M Zisterer, Seema Nathwani, D Clive Williams, Giuseppe Campiani, Maurizio Bifulco
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 714 Issue 1-3 Pg. 379-87 (Aug 15 2013) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 23872382 (Publication Type: Journal Article, Retracted Publication)
• Copyright: © 2013 Elsevier B.V. All rights reserved.