title: 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.affiliation: Department of Pharmacy, University of Salerno, 84084 Fisciano, SA, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Gangemi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gazzerro
authors.forename: Donatella
authors.initials: D
authors.lastname: Fiore
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Proto
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Alice
authors.initials: A
authors.lastname: Casagni
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.forename: Mario
authors.initials: M
authors.lastname: Vitale
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Seema
authors.initials: S
authors.lastname: Nathwani
authors.forename: D
authors.initials: D
authors.lastname: Clive Williams
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
keywords: Colorectal cancer; Combinatorial effect; FAAH inhibitor; Pyrrolo-1,5-benzoxazepine