title: Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells.
abstract: Some compounds of a series of novel pyrrolo-1,5-benzoxa(thia)zepine, a well-known group of tubulin targeting agents, display anti-tumor 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 toward 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 1 μM, 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.
authors.affiliation: a Department of Pharmacy , University of Salerno , Fisciano (SA) , Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Fiore
authors.affiliation: a Department of Pharmacy , University of Salerno , Fisciano (SA) , Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Proto
authors.affiliation: a Department of Pharmacy , University of Salerno , Fisciano (SA) , Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pisanti
authors.affiliation: a Department of Pharmacy , University of Salerno , Fisciano (SA) , Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Picardi
authors.affiliation: a Department of Pharmacy , University of Salerno , Fisciano (SA) , Italy.
authors.forename: Antonio Christian
authors.initials: AC
authors.lastname: Pagano Zottola
authors.affiliation: b European Research Center for Drug Discovery and Development (NatSynDrugs) and Dip. di Biotecnologie , Chimica e Farmacia, University of Siena , Siena , Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.affiliation: b European Research Center for Drug Discovery and Development (NatSynDrugs) and Dip. di Biotecnologie , Chimica e Farmacia, University of Siena , Siena , Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.affiliation: b European Research Center for Drug Discovery and Development (NatSynDrugs) and Dip. di Biotecnologie , Chimica e Farmacia, University of Siena , Siena , Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Casagni
authors.affiliation: c Institute of Endocrinology and Experimental Oncology, IEOS CNR , Naples , Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.affiliation: d Department of Medicine and Surgery , University of Salerno , Baronissi (SA) , Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Vitale
authors.affiliation: e Institute of Biomolecular Chemistry, C.N.R. , Pozzuoli (Naples) , Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.affiliation: e Institute of Biomolecular Chemistry, C.N.R. , Pozzuoli (Naples) , Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: f School of Biochemistry and Immunology , Trinity College Dublin , Dublin , Ireland.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.affiliation: f School of Biochemistry and Immunology , Trinity College Dublin , Dublin , Ireland.
authors.forename: Seema
authors.initials: S
authors.lastname: Nathwani
authors.affiliation: f School of Biochemistry and Immunology , Trinity College Dublin , Dublin , Ireland.
authors.forename: D Clive
authors.initials: DC
authors.lastname: Williams
authors.affiliation: b European Research Center for Drug Discovery and Development (NatSynDrugs) and Dip. di Biotecnologie , Chimica e Farmacia, University of Siena , Siena , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.affiliation: a Department of Pharmacy , University of Salerno , Fisciano (SA) , Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gazzerro
authors.affiliation: d Department of Medicine and Surgery , University of Salerno , Baronissi (SA) , Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077150:Oxaliplatin; D010077:Oxazepines / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C514160:4-acetoxy-5-(1-(naphthyl))naphtho(2,3-b)pyrrolo(2,1-d)(1,4)oxazepine; D009944:Organoplatinum Compounds; D010077:Oxazepines; D011758:Pyrroles; D000077150:Oxaliplatin; D005472:Fluorouracil
keywords: 5-Fluorouracil; FAAH inhibitors; colorectal cancer; combinatorial effect; oxaliplatin; pyrrolo-1,5-benzoxazepine