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

PLOS ONE, Dec 2019

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

et al. (2013) 5-Aminolevulinic Acid Protects against Cisplatin-Induced Nephrotoxicity without Compromising the Anticancer Efficiency of Cisplatin in Rats In Vitro and In Vivo. PLoS ONE 8(12): e80850. doi:10.1371/journal.pone.0080850 5-Aminolevulinic Acid Protects against Cisplatin-Induced Nephrotoxicity without Compromising the Anticancer Efficiency of Cisplatin in Rats In Vitro and In Vivo Yoshio Terada 0 Keiji Inoue 0 Tatsuki Matsumoto 0 Masayuki Ishihara 0 Kazu Hamada 0 Yoshiko Shimamura 0 Koji Ogata 0 Kosuke Inoue 0 Yoshinori Taniguchi 0 Taro Horino 0 Takashi Karashima 0 Kenji Tamura 0 Hideo Fukuhara 0 Shimpei Fujimoto 0 Masayuki Tsuda 0 Taro Shuin 0 Jeff M. Sands, Emory University, United States of America 0 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 Background/Aims: Nephrotoxicity is a frequent and major limitation in cisplatin (CDDP)-based chemotherapy. 5Aminolevulinic 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 ATP5a, complex(COX) IV, UCP2, PGC-1a 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. - 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. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Cisplatin is one of the most effective and potent anticancer drugs in the treatment of epithelial malignancies such as lung, head and neck, ovarian, bladder, and testicular cancers [1]. The major constraint to cisplatin-based chemotherapy is the frequent development of nephrotoxicity [2]. The antineoplastic effect of cisplatin is dose dependent, yet the risk of nephrotoxicity often precludes the use of higher doses to maximize the therapeutic effect. Cisplatin induces apoptosis of renal proximal tubule cells (LLC-PK1) in vitro by means of mitochondria-dependent and independent pathways [3], partly through the activation of caspase-3 [4]. Oxidant stress also appears to contribute to the cisplatin-induced apoptosis of renal tubular cells, both in vitro and in vivo [5]. Several studies, including ours, suggest that caspase inhibitors and knockout of apoptosis-related genes attenuate cisplatin-induced acute kidney injury (AKI) in rats [6,7]. Mitochondria have a variety of important intracellular functions, including ATP production, synthesis of reactive oxygen species, and regulation of the cell death pathway. Recent studies, including ours, have demonstrated that mitochondrial function is one of the key factors protecting cells from oxidative stress in AKI [8,9]. Figure 1. Blood urea nitrogen (BUN) and serum creatinine (Cre) levels in ALA treated rats afte (...truncated)


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Yoshio Terada, Keiji Inoue, Tatsuki Matsumoto, Masayuki Ishihara, Kazu Hamada, Yoshiko Shimamura, Koji Ogata, Kosuke Inoue, Yoshinori Taniguchi, Taro Horino, Takashi Karashima, Kenji Tamura, Hideo Fukuhara, Shimpei Fujimoto, Masayuki Tsuda, Taro Shuin. 5-Aminolevulinic Acid Protects against Cisplatin-Induced Nephrotoxicity without Compromising the Anticancer Efficiency of Cisplatin in Rats In Vitro and In Vivo, PLOS ONE, 2013, 12, DOI: 10.1371/journal.pone.0080850