title: Different apoptotic pathways activated by oxaliplatin in primary astrocytes vs. colo-rectal cancer cells.
abstract: Oxaliplatin-based chemotherapy improves the outcomes of metastatic colorectal cancer patients. Its most significant and dose-limiting side effect is the development of a neuropathic syndrome. The mechanism of the neurotoxicity is unclear. The limited knowledge about differences existing between neurotoxic and antitumor effects hinders the discovery of effective and safe adjuvant therapies. In vitro, we suggested cell-specific activation apoptotic pathways in normal nervous cells (astrocytes) vs. colon-cancer cells (HT-29). In the present research we compared the apoptotic signals evoked by oxaliplatin in astrocytes and HT-29 analyzing the intrinsic and extrinsic apoptotic pathways. In astrocytes, oxaliplatin induced a mitochondrial derangement measured as cytosolic release of cytochrome C, increase in superoxide anion levels and decreased expression of the antiapoptotic protein Bcl-2. Caspase-8, a main initiator of the extrinsic process remained unaltered. On the contrary, in HT-29 oxaliplatin increased caspase-8 activity and Bid expression, thus activating the extrinsic apoptosis, while the Bcl-2 increased expression blocked the mitochondrial damage. Data suggest the preferred activation of the intrinsic apoptosis as oxaliplatin damage signaling in normal nervous cells. The extrinsic pathway prevails in tumor cells indicating a possible strategy for planning new molecules to treat oxaliplatin-dependent neurotoxicity without negatively influence chemotherapy.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence 50139, Italy. matteo.zanardelli@unifi.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Zanardelli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence 50139, Italy. laura.micheli@unifi.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina km 30,400, I-00040 Pomezia, Rome 00040, Italy. Raffaella.Nicolai@sigma-tau.it.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Nicolai
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence 50139, Italy. paola.failli@unifi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Failli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence 50139, Italy. carla.ghelardini@unifi.it.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence 50139, Italy. lorenzo.mannelli@unifi.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000633:toxicity; D000077150:Oxaliplatin; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin