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Int. J. Mol. Sci. 2015, 16(3), 5386-5399; doi:10.3390/ijms16035386

Different Apoptotic Pathways Activated by Oxaliplatin in Primary Astrocytes vs. Colo-Rectal Cancer Cells

1
Department of Neuroscience, Psychology, Drug Research and Child Health – Neurofarba – Pharmacology and Toxicology Section, University of Florence, Florence 50139, Italy
2
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina km 30,400, I-00040 Pomezia, Rome 00040, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Ritva Tikkanen
Received: 22 January 2015 / Revised: 28 February 2015 / Accepted: 2 March 2015 / Published: 9 March 2015
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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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. View Full-Text
Keywords: glia; HT-29; neuropathic pain; intrinsic apoptotic pathway; extrinsic apoptotic pathway; oxaliplatin glia; HT-29; neuropathic pain; intrinsic apoptotic pathway; extrinsic apoptotic pathway; oxaliplatin
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Zanardelli, M.; Micheli, L.; Nicolai, R.; Failli, P.; Ghelardini, C.; Di Cesare Mannelli, L. Different Apoptotic Pathways Activated by Oxaliplatin in Primary Astrocytes vs. Colo-Rectal Cancer Cells. Int. J. Mol. Sci. 2015, 16, 5386-5399.

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