3 results on '"combinatorial effect"'
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2. PBOX-15 induces apoptosis and improves the efficacy of oxaliplatin in human colorectal cancer cell lines.
- Author
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Gangemi, Giuseppina, Gazzerro, Patrizia, Fiore, Donatella, Proto, Maria Chiara, Butini, Stefania, Gemma, Sandra, Casagni, Alice, Laezza, Chiara, Vitale, Mario, Ligresti, Alessia, Di Marzo, Vincenzo, Zisterer, Daniela M., Nathwani, Seema, Clive Williams, D., Campiani, Giuseppe, and Bifulco, Maurizio
- Subjects
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APOPTOSIS , *OXALIPLATIN , *DRUG efficacy , *COLON cancer treatment , *CANCER cells , *CELL lines , *TARGETED drug delivery - Abstract
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 1μM 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 48h 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. [Copyright &y& Elsevier]
- Published
- 2013
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3. Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells
- Author
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Maria Proto, Alice Casagni, D. Clive Williams, Antonio Christian Pagano Zottola, Mario Vitale, Daniela M. Zisterer, Vincenzo Di Marzo, Paola Picardi, Chiara Laezza, Donatella Fiore, Stefania Butini, Maurizio Bifulco, Patrizia Gazzerro, Giuseppe Campiani, Simona Pisanti, Alessia Ligresti, Sandra Gemma, Seema M. Nathwani, Fiore, Donatella, Proto, MARIA CHIARA, Pisanti, Simona, Picardi, Paola, PAGANO ZOTTOLA, ANTONIO CHRISTIAN, Butini, Stefania, Gemma, Sandra, Casagni, Alica, Laezza, Chiara, Vitale, Mario, Ligresti, Alessia, Di Marzo, Vincenzo, Zisterer, Daniela M, Nathwanid, Seema, Williams, Cleeve D, Campiani, Giuseppe, Gazzerro, Patrizia, and Bifulco, Maurizio
- Subjects
0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,Organoplatinum Compounds ,Colorectal cancer ,Cell ,5-benzoxazepine ,Apoptosis ,Pharmacology ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Drug Synergism ,Keywords Pyrrolo-1 ,medicine.anatomical_structure ,Oncology ,pyrrolo-1 ,030220 oncology & carcinogenesis ,Molecular Medicine ,Fluorouracil ,Colorectal Neoplasms ,HT29 Cells ,medicine.drug ,Research Paper ,Cell type ,5-Fluorouracil ,FAAH inhibitors ,colorectal cancer ,03 medical and health sciences ,combinatorial effect ,oxaliplatin ,pyrrolo-1,5-benzoxazepine ,Cell Line, Tumor ,Humans ,Pyrroles ,Cell Proliferation ,Oxaliplatin ,Pyrrolo-1 ,business.industry ,Cell growth ,Cell Cycle Checkpoints ,medicine.disease ,Oxazepines ,030104 developmental biology ,Cell culture ,Pyrrolo-1,5-benzoxazepine ,business - Abstract
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 1?M, 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.
- Published
- 2016
- Full Text
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