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• W2021609364 abstract "EDITORIAL FOCUSCisplatin-induced cytoxicity: is the nucleus relevant?David Sheikh-HamadDavid Sheikh-HamadPublished Online:01 Jul 2008https://doi.org/10.1152/ajprenal.90293.2008This is the final version - click for previous versionMoreSectionsPDF (44 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat cisplatin is a potent chemotherapeutic agent widely used for the treatment of cancer. However, cisplatin is frequently associated with nephrotoxicity, manifesting as acute kidney injury accompanied by hypokalemia and hypomagnesemia (6). Overdose of cisplatin has been reported to cause a wide array of effects, including kidney and liver failure, myelosuppression, neuropathy, ototoxicity, and blindness (16). Cisplatin nephrotoxicity is dose dependent and may correlate with the cumulative dose of the drug (4, 14). The exact mechanism by which cisplatin produces renal damage is unknown. After a single dose of cisplatin, there is preferential sequestration of the drug in the kidneys, liver, intestine, and testes, with concentrations in the kidneys reaching levels higher than 37 times those in plasma (9). Morphological changes after cisplatin-induced kidney injury are most prominent in S3 segments of proximal tubules, where loss of brush-border membrane, cell swelling, nuclear condensation, and focal areas of tubular cell apoptosis and necrosis are seen (15). The reasons for the selective injury of S3 segments after cisplatin administration are unclear. It was hypothesized by Dobyan et al. (3) that cisplatin accumulates selectively in S3 segments secondary to secretion by the adjacent pars recta; alternatively, hemodynamic changes caused by cisplatin may lead to decreased circulation in the vasa recta, causing damage to the most susceptible adjacent regions that include S3 segments.Cisplatin induces damage to tumors via induction of apoptosis; this is mediated by activation of death receptor-mediated apoptotic signaling mechanisms as well as mitochondrial pathways (2). In addition, cisplatin causes DNA cross-linking, inhibiting cell proliferation (20). However, cisplatin also binds to plasma and cellular proteins, accounting for the difficulty in clearing the drug from the circulation and tissue. Of note, the drug binds irreversibly to sulfhydryl groups of low- and high-molecular-weight molecules (10), and this binding correlates with a fall in the concentration of sulfhydryl moieties in the kidney, especially in the mitochondrial and cytosolic fractions (8), inhibiting a number of sulfhydryl-containing enzymes, including ATPases, thymidylate synthetase, glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, γ-glutamylcysteine synthetase, and ribonucleotide reductase (1). The depletion of sulfhydryl groups, which include glutathione, may alter the redox state and contribute to cisplatin-induced cytotoxicity. Thus the toxicity of cisplatin may result from a combination of factors that include, but may not be limited to DNA cross-linking, inhibition of enzymatic activity, and depletion of the antioxidant pool.In an interesting and elegant work, Yu et al. (19) demonstrate that cisplatin initiates apoptosis from the cytoplasm and suggest that nuclear events may not be critical for the initiation of cisplatin-induced cytotoxicity, at least, not in kidney cells. Cumulative data from this group have demonstrated the involvement of CDK2 in cisplatin-induced cell death in vivo and in vitro (13, 18), and inhibition of CDK2 by p21 protects from cisplatin-induced injury (11, 12, 17). Of interest, deletion of the nuclear localization signal from p21 does not alter its protective action against cisplatin cytotoxicity (17), suggesting that the protective interaction between p21 and CDK2 may not occur in the nucleus. Indeed, active cdk2-cyclin complexes are detected in both nucleus and cytoplasm (7), and translocation of cdk2 from the nucleus to the cytoplasm was reported to occur after the apoptotic stimulus (5). This finding is intriguing, as CDK2 is a cell cycle regulator, and by default, active CDK2 is expected to reside in the nucleus. Yu et al. (19) demonstrate the presence of cdk2 activity in cytoplasts, and as was observed in nucleated cells (13, 18), inhibition of cdk2 in cytoplasts blocked cisplatin-induced apoptosis. These data suggest that cisplatin-induced apoptosis may be initiated from the cytoplasm, in a manner that does not require nuclear contribution. Additionally, they find that cdk2 localizes to the ER and Golgi compartments, suggesting that phosphorylation of substrates in these compartments by CDK2 in response to cisplatin may play an important role in cisplatin-induced cytotoxicity and that CDK2 activity may be critical for cell death signaling originating from the endoplasmic reticulum (ER). Accordingly, inhibition of CDK2 in cytoplasts attenuates ER stress induced by various stressors, such as tunicamycin, which inhibits N-glycosylation, brefeldin A, which causes disassembly of the Golgi and accumulation of secretory proteins in the ER, and thapsigargin, which inhibits the ER Ca2+-ATPase.Cumulatively, the data by Yu et al. (19) demonstrate that while cisplatin cytotoxicity may be augmented by nuclear events, it may be initiated from the cytoplasm; cdk2 activity, which normally promotes cell cycle progression, is important for promoting apoptosis in response to cisplatin; and finally, subcellular localization of cdk2 may determine its substrate specificity, which in turn determines cell fate. Thus CDK2 may regulate a critical checkpoint in stressed cells; determining whether the cells are viable, and hence can proliferate, or are damaged, and hence committed to apoptosis.REFERENCES1 Anderson ME, Naganuma A, Meister A. Protection against cisplatin toxicity by administration of glutathione ester. FASEB J 4: 3251–3255, 1990.Crossref | PubMed | ISI | Google Scholar2 Boulikas T, Vougiouka M. Cisplatin and platinum drugs at the molecular level. Oncol Rep 10: 1663–1682, 2003.PubMed | ISI | Google Scholar3 Dobyan DC, Levi J, Jacobs C, Kosek J, Weiner MW. Mechanism of cis-platinum nephrotoxicity. II. Morphologic observations. J Pharmacol Exp Ther 213: 551–556, 1980.PubMed | ISI | Google Scholar4 Goren MP, Wright RK, Horowitz ME. Cumulative renal tubular damage associated with cisplatin nephrotoxicity. Cancer Chemother Pharmacol 18: 69–73, 1986.Crossref | PubMed | ISI | Google Scholar5 Hiromura K, Pippin JW, Blonski MJ, Roberts JM, Shankland SJ. The subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation. Oncogene 21: 1750–1758, 2002.Crossref | PubMed | ISI | Google Scholar6 Jones DP, Chesney RW. 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Biopharm Drug Dispos 2: 1–16, 1981.Crossref | PubMed | ISI | Google Scholar11 Megyesi J, Safirstein RL, Price PM. Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure. J Clin Invest 101: 777–782, 1998.Crossref | PubMed | ISI | Google Scholar12 Price PM, Safirstein RL, Megyesi J. Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. Am J Physiol Renal Physiol 286: F378–F384, 2004.Link | ISI | Google Scholar13 Price PM, Yu F, Kaldis P, Aleem E, Nowak G, Safirstein RL, Megyesi J. Dependence of cisplatin-induced cell death in vitro and in vivo on cyclin-dependent kinase 2. J Am Soc Nephrol 17: 2434–2442, 2006.Crossref | PubMed | ISI | Google Scholar14 Ries F, Klastersky J. Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis 8: 368–379, 1986.Crossref | PubMed | ISI | Google Scholar15 Sheikh-Hamad D, Cacini W, Buckley AR, Isaac J, Truong LD, Tsao CC, Kishore BK. Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney. Arch Toxicol 78: 147–155, 2004.Crossref | PubMed | ISI | Google Scholar16 Sheikh-Hamad D, Timmins K, Jalali Z. Cisplatin-induced renal toxicity: possible reversal by N-acetylcysteine treatment. J Am Soc Nephrol 8: 1640–1644, 1997.PubMed | ISI | Google Scholar17 Yu F, Megyesi J, Safirstein RL, Price PM. Identification of the functional domain of p21(WAF1/CIP1) that protects cells from cisplatin cytotoxicity. Am J Physiol Renal Physiol 289: F514–F520, 2005.Link | ISI | Google Scholar18 Yu F, Megyesi J, Safirstein RL, Price PM. Involvement of the CDK2-E2F1 pathway in cisplatin cytotoxicity in vitro and in vivo. Am J Physiol Renal Physiol 293: F52–F59, 2007.Link | ISI | Google Scholar19 Yu F, Megyesi JK, Price PM. Cytoplasmic initiation of cisplatin cytotoxicity. Am J Physiol Renal Physiol (First published April 9, 2008). doi:10.1152/ajprenal.00593.2007.Link | ISI | Google Scholar20 Zwelling LA, Kohn KW, Ross WE, Ewig RA, Anderson T. Kinetics of formation and disappearance of a DNA cross-linking effect in mouse leukemia L1210 cells treated with cis- and trans-diamminedichloroplatinum(II). Cancer Res 38: 1762–1768, 1978.PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: D. Sheikh-Hamad, Div. of Nephrology, Dept. of Medicine, Baylor College of Medicine, Houston, TX (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByFacile synthesis of heterobimetallic [FeII(µ-diphosphine)RuII] and homobimetallic [FeII(µ-diphosphine)FeII] complexes and their in vitro cytotoxic activity on cisplatin-resistant cancer cellsInorganica Chimica Acta, Vol. 510The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in miceCellular Signalling, Vol. 71Enolate-forming compounds provide protection from platinum neurotoxicityChemico-Biological Interactions, Vol. 317Introduction19 June 2018Honey protects against cisplatin-induced hepatic and renal toxicity through inhibition of NF-κB-mediated COX-2 expression and the oxidative stress dependent BAX/Bcl-2/caspase-3 apoptotic pathway1 January 2018 | Food & Function, Vol. 9, No. 7Effect of diabetes on biodistribution, nephrotoxicity and antitumor activity of cisplatin in miceChemico-Biological Interactions, Vol. 229Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain13 September 2013 | Journal of Neuro-Oncology, Vol. 115, No. 3Synthesis, X-ray structure, interactions with DNA, remarkable in vivo tumor growth suppression and nephroprotective activity of cis-tetrachloro-dipivalato dirhenium(III)Journal of Inorganic Biochemistry, Vol. 129ER signaling regulation drives the switch between autophagy and apoptosis in NRK-52E cells exposed to cisplatinExperimental Cell Research, Vol. 318, No. 3Environmental and Drug Induced Renal Damage; The Way to Protect5 January 2012IL-33 Exacerbates Acute Kidney InjuryJournal of the American Society of Nephrology, Vol. 22, No. 11The Challenge of Establishing Reliable Screening Tests for Selecting Anticancer Metal Compounds23 February 2011Mechanistic insight into the cellular uptake and processing of cisplatin 30 years after its approval by FDACoordination Chemistry Reviews, Vol. 253, No. 15-16The Kidney and Ear: Emerging Parallel FunctionsAnnual Review of Medicine, Vol. 60, No. 1 More from this issue > Volume 295Issue 1July 2008Pages F42-F43 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.90293.2008PubMed18480173History Published online 1 July 2008 Published in print 1 July 2008 Metrics" @default.
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