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Title: Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells
Authors: Fiore, Donatella
Proto, Maria Chiara
Pisanti, Simona
Picardi, Paola
Pagano Zottola, Antonio Christian
Butini, Stefania 
Gemma, Sandra 
Casagni, Alice
Laezza, Chiara
Vitale, Mario
Ligresti, Alessia
Di Marzo, Vincenzo
Zisterer, Daniela M
Nathwani, Seema
Williams, D Clive
Campiani, Giuseppe 
Gazzerro, Patrizia
Bifulco, Maurizio
Keywords: 5-Fluorouracil; FAAH inhibitors; Oxaliplatin; Pyrrolo-1,5-benzoxazepine; colorectal cancer; combinatorial effect
Issue Date: 2016
Project: None 
Some compounds of a series of novel pyrrolo-1,5-benzoxa(thia)zepine, a well-known group of tubulin targeting agents, display anti-tumour effects mainly inducing cell cycle arrest and apoptosis in several human cancer models. A member of this family, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), has previously shown potent pro-apoptotic activity in a variety of human tumor cell types, 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, DLD-1 and HT-29. The compound, used at concentrations equal to or greater than 1μM, inhibited the proliferation of human CRC cells, inducing a significant cell cycle arrest in the G2/M phase. In DLD-1 cells, treatments prolonged over 48 h triggered a strong activation of the intrinsic apoptotic pathway as indicated by activation of caspase-9, caspase-3 and PARP cleavage. Moreover, nanomolar concentrations of PBOX-15, significantly improved the oxaliplatin and 5-fluouracil-induced anti-proliferative effects in DLD1 cell line. The observed synergistic interaction of both PBOX-15/Oxaliplatin and PBOX-15/5FU may involve activation of p38 MAPK and JNK pathway, which in turn significantly increased caspase-3 cleavage in DLD-1 cells, treated with PBOX-5/Oxaliplatin but not with PBOX-15/5FU. Moreover, PBOX-15/5FU-treated cells showed an increase in expression of the pro-apoptotic protein Bax. Taken together, these results show that PBOX-15 could represent a promising compound for the treatment of human CRC and a strong candidate for novel therapeutic options.
ISSN: 1538-4047
DOI: 10.1080/15384047.2015.1078028
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