| Mitochondrial/lysosomal toxic cross-talk plays a key role in cisplatin nephrotoxicity. | |
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MedLine Citation:
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PMID: 20809784 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cisplatin is widely used chemotherapeutic agent for the treatment of several human malignancies. Dose-related nephrotoxicity is the major adverse effect of cisplatin. The cellular and molecular mechanisms behind the cisplatin nephrotoxicity have not yet been completely understood. In this study, cytotoxic effect of cisplatin on renal proximal tubular (RPT) cells was evaluated. Our results showed that cytotoxic action of cisplatin on RPT cells is mediated by reactive oxygen species (ROS) formation, decline of mitochondrial membrane potential, increase in caspase-3 activity and lysosomal membrane leakiness before cell lysis ensued. All of the above mentioned cisplatin-induced oxidative stress cytotoxicity markers were significantly (p < 0.05) prevented by ROS scavengers, antioxidants, mitochondrial permeability transition (MPT) pore sealing agents, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Our results also showed that CYP2E1 involves in cisplatin oxidative stress cytotoxicity mechanism and intracellular nitric oxide enhancement protects the RPT cells against the cisplatin-induced cytotoxicity. It seems that cisplatin nephrotoxicity is associated with mutual mitochondrial/lysosomal potentiation (cross-talk) of oxidative stress in RPT cells. This cross-talk finally results in release of lysosomal digestive proteases and phospholipases and mitochondrial MPT pore opening leading to cytochrome c release and activation of caspases cascade which signal apoptosis. |
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Authors:
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Jalal Pourahmad; Mir-Jamal Hosseini; Mohammad Reza Eskandari; Seyed Mohammad Shekarabi; Bahram Daraei |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Xenobiotica; the fate of foreign compounds in biological systems Volume: 40 ISSN: 1366-5928 ISO Abbreviation: Xenobiotica Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-12 Completed Date: 2011-01-27 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1306665 Medline TA: Xenobiotica Country: England |
Other Details:
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Languages: eng Pagination: 763-71 Citation Subset: IM |
Affiliation:
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Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran. j.pourahmadjaktaji@utoronto.ca |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / toxicity* Caspase 3 / metabolism Cells, Cultured Cisplatin / toxicity* Kidney Diseases / chemically induced*, metabolism Kidney Tubules, Proximal / drug effects, metabolism Lysosomes / drug effects Male Membrane Potential, Mitochondrial / drug effects* Oxidative Stress / drug effects Rats Rats, Sprague-Dawley Reactive Oxygen Species / metabolism* Receptor Cross-Talk / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Reactive Oxygen Species; 15663-27-1/Cisplatin; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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