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      5-Aminolevulinic Acid Protects against Cisplatin-Induced Nephrotoxicity without Compromising the Anticancer Efficiency of Cisplatin in Rats In Vitro and In Vivo

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          Abstract

          Background/Aims

          Nephrotoxicity is a frequent and major limitation in cisplatin (CDDP)-based chemotherapy. 5-Aminolevulinic acid (ALA) is widely distributed in animal cells, and it is a precursor of tetrapyrole compounds such as heme that is fundamentally important in aerobic energy metabolism. The aim of this study is to evaluate the protective role of ALA in CDDP-induced acute kidney injury (AKI).

          Method

          We used CDDP-induced AKI rat model and cultured renal tubular cells (NRK-52E). We divided four groups of rats: control, CDDP only, CDDP + ALA(post);(ALA 10 mg/kg + Fe in drinking water) after CDDP, CDDP + ALA(pre & post).

          Result

          CDDP increased Cr up to 6.5 mg/dl, BUN up to 230 mg/dl, and ALA significantly reduced these changes. ALA ameliorates CDDP-induced morphological renal damages, and reduced tubular apoptosis evaluated by TUNEL staining and cleaved caspase 3. Protein and mRNA levels of ATP5α, complex(COX) IV, UCP2, PGC-1α in renal tissue were significantly decreased by CDDP, and ALA ameliorates reduction of these enzymes. In contrast, Heme Oxigenase (HO)-1 level is induced by CDDP treatment, and ALA treatment further up-regulates HO-1 levels. In NRK-52E cells, the CDDP-induced reduction of protein and mRNA levels of mitochondrial enzymes was significantly recovered by ALA + Fe. CDDP-induced apoptosis were ameliorated by ALA + Fe treatment. Furthermore, we evaluated the size of transplantated bladder carcinoma to the rat skin, and ALA did not change the anti cancer effects of CDDP.

          Conclusion

          These data suggested that the protective role of ALA in cisplatin-induced AKI is via protection of mitochondrial viability and prevents tubular apoptosis. Also there are no significant effects of ALA on anticancer efficiency of CDDP in rats. Thus, ALA has the potential to prevent CDDP nephrotoxicity without compromising its anticancer efficacy.

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          Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.

          William Rosenberg, Rahul Nath, Reeba Jacob … (1992)
          Heme proteins such as myoglobin or hemoglobin, when released into the extracellular space, can instigate tissue toxicity. Myoglobin is directly implicated in the pathogenesis of renal failure in rhabdomyolysis. In the glycerol model of this syndrome, we demonstrate that the kidney responds to such inordinate amounts of heme proteins by inducing the heme-degradative enzyme, heme oxygenase, as well as increasing the synthesis of ferritin, the major cellular repository for iron. Prior recruitment of this response with a single preinfusion of hemoglobin prevents kidney failure and drastically reduces mortality (from 100% to 14%). Conversely, ablating this response with a competitive inhibitor of heme oxygenase exacerbates kidney dysfunction. We provide the first in vivo evidence that induction of heme oxygenase coupled to ferritin synthesis is a rapid, protective antioxidant response. Our findings suggest a therapeutic strategy for populations at a high risk for rhabdomyolysis.
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            Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation.

            W Buurman, Joaquim Van-Dunem, M Daemen … (1999)
            Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of tissue injury in organs subjected to ischemia. The mechanism that triggers inflammation and organ injury after ischemia remains to be elucidated, although different causes have been postulated. We investigated the role of apoptosis in the induction of inflammation and organ damage after renal ischemia. Using a murine model, we demonstrate a relationship between apoptosis and subsequent inflammation. At the time of reperfusion, administration of the antiapoptotic agents IGF-1 and ZVAD-fmk (a caspase inactivator) prevented the early onset of not only renal apoptosis, but also inflammation and tissue injury. Conversely, when the antiapoptotic agents were administered after onset of apoptosis, these protective effects were completely abrogated. The presence of apoptosis was directly correlated with posttranslational processing of the endothelial monocyte-activating polypeptide II (EMAP-II), which may explain apoptosis-induced influx and sequestration of leukocytes in the reperfused kidney. These results strongly suggest that apoptosis is a crucial event that can initiate reperfusion-induced inflammation and subsequent tissue injury. The newly described pathophysiological insights provide important opportunities to effectively prevent clinical manifestations of reperfusion injury in the kidney, and potentially in other organs.
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              Cisplatin and platinum drugs at the molecular level. (Review).

              Teni Boulikas, Maria Vougiouka (2015)
              Over twenty years of intensive work toward improvement of cisplatin, and with hundreds of platinum drugs tested, has resulted in the introduction of the widely used carboplatin and of oxaliplatin used only for a very narrow spectrum of cancers. A number of interesting platinum compounds including the orally administered platinum drug JM216, nedaplatin, the sterically hindered platinum(II) complex ZD0473, the trinuclear platinum complex BBR3464, and the liposomal forms Lipoplatin and SPI-77 are under clinical evaluation. This review summarizes the molecular mechanisms of platinum compounds for DNA damage, DNA repair and induction of apoptosis via activation or modulation of signaling pathways and explores the basis of platinum resistance. Cisplatin, carboplatin, oxaliplatin and most other platinum compounds induce damage to tumors via induction of apoptosis; this is mediated by activation of signal transduction leading to the death receptor mechanisms as well as mitochondrial pathways. Apoptosis is responsible for the characteristic nephrotoxicity, ototoxicity and most other toxicities of the drugs. The major limitation in the clinical applications of cisplatin has been the development of cisplatin resistance by tumors. Mechanisms explaining cisplatin resistance include the reduction in cisplatin accumulation inside cancer cells because of barriers across the cell membrane, the faster repair of cisplatin adducts, the modulation of apoptotic pathways in various cells, the upregulation in transcription factors, the loss of p53 and other protein functions and a higher concentration of glutathione and metallothioneins in some type of tumors. A number of experimental strategies to overcome cisplatin resistance are at the preclinical or clinical level such as introduction of the bax gene, inhibition of the JNK pathway, introduction of a functional p53 gene, treatment of tumors with aldose reductase inhibitors and others. Particularly important are combinations of platinum drug treatments with other drugs, radiation and the emerging gene therapy regimens.
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                Author and article information

                Contributors
                Jeff M. Sands: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 6 December 2013
                Volume: 8
                Issue: 12
                Electronic Location Identifier: e80850
                Affiliations
                [1 ]Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Japan
                [2 ]Department of Urology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Japan
                [3 ]Institute for Laboratory Animal Research, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Japan
                Emory University, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: Y. Terada Keiji Inoue MT, TS. Performed the experiments: Y. Terada Keiji Inoue TM MI KH YS KO Kosuke Inoue Y. Taniguchi TH TK KT HF SF MT. Analyzed the data: Y. Terada Keiji Inoue TM MI KH YS TK KT HF SF MT. Contributed reagents/materials/analysis tools: Y. Terada Keiji Inoue MT TS. Wrote the paper: Y. Terada Keiji Inoue TS.

                Article
                Publisher ID: PONE-D-13-32442
                DOI: 10.1371/journal.pone.0080850
                PMC ID: 3855642
                SO-VID: 640b13c5-6990-4c3a-b474-1719a1622cec
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 7 August 2013
                Date accepted : 13 October 2013
                Page count
                Pages: 12
                Funding
                This work was supported by The Kidney Foundation Japan and the Kochi organization for medical reformation and renewal (to YT); grants from the Ministry of Education, Science, Culture and Sports of Japan (to YT, KI, YS, KI, SF, TS); and a grant-in-aid for Progressive Renal Diseases Research, Research on Rare and Intractable Disease, from the Ministry of Health, Labour and Welfare of Japan (to YT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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