5-Aminolevulinic Acid Protects Against Cisplatin-induced Nephrotoxicity Without Compromising the Anticancer Efficiency of Cisplatin in Rats in Vitro and in Vivo

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Dec 11

PMID 24324635

Citations 20

Authors

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

Affiliations

Soon will be listed here.

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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References

Terada Y, Tanaka H, Okado T, Shimamura H, Inoshita S, Kuwahara M . Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats. J Am Soc Nephrol. 2003; 14(5):1223-33. DOI: 10.1097/01.asn.0000060577.94532.06. View

Park M, De Leon M, Devarajan P . Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways. J Am Soc Nephrol. 2002; 13(4):858-865. DOI: 10.1681/ASN.V134858. View

Zhou H, Miyaji T, Kato A, Fujigaki Y, Sano K, Hishida A . Attenuation of cisplatin-induced acute renal failure is associated with less apoptotic cell death. J Lab Clin Med. 1999; 134(6):649-58. DOI: 10.1016/s0022-2143(99)90106-3. View

Arany I, Safirstein R . Cisplatin nephrotoxicity. Semin Nephrol. 2003; 23(5):460-4. DOI: 10.1016/s0270-9295(03)00089-5. View

Tanabe K, Tamura Y, Lanaspa M, Miyazaki M, Suzuki N, Sato W . Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy. Am J Physiol Renal Physiol. 2012; 303(9):F1264-74. PMC: 5243204. DOI: 10.1152/ajprenal.00227.2012. View

Safirstein R, Winston J, Goldstein M, Moel D, Dikman S, Guttenplan J . Cisplatin nephrotoxicity. Am J Kidney Dis. 1986; 8(5):356-67. DOI: 10.1016/s0272-6386(86)80111-1. View

Inoue K, Kuwana H, Shimamura Y, Ogata K, Taniguchi Y, Kagawa T . Cisplatin-induced macroautophagy occurs prior to apoptosis in proximal tubules in vivo. Clin Exp Nephrol. 2009; 14(2):112-22. DOI: 10.1007/s10157-009-0254-7. View

Ishizuka M, Abe F, Sano Y, Takahashi K, Inoue K, Nakajima M . Novel development of 5-aminolevurinic acid (ALA) in cancer diagnoses and therapy. Int Immunopharmacol. 2010; 11(3):358-65. DOI: 10.1016/j.intimp.2010.11.029. View

Ogura S, Maruyama K, Hagiya Y, Sugiyama Y, Tsuchiya K, Takahashi K . The effect of 5-aminolevulinic acid on cytochrome c oxidase activity in mouse liver. BMC Res Notes. 2011; 4:66. PMC: 3068109. DOI: 10.1186/1756-0500-4-66. View

10.

Hall A, Rhodes G, Sandoval R, Corridon P, Molitoris B . In vivo multiphoton imaging of mitochondrial structure and function during acute kidney injury. Kidney Int. 2012; 83(1):72-83. PMC: 4136483. DOI: 10.1038/ki.2012.328. View

11.

Kaushal G, Kaushal V, Hong X, Shah S . Role and regulation of activation of caspases in cisplatin-induced injury to renal tubular epithelial cells. Kidney Int. 2001; 60(5):1726-36. DOI: 10.1046/j.1523-1755.2001.00026.x. View

12.

Abraham N, Kappas A . Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev. 2008; 60(1):79-127. DOI: 10.1124/pr.107.07104. View

13.

Brady H, Kone B, Stromski M, Zeidel M, Giebisch G, Gullans S . Mitochondrial injury: an early event in cisplatin toxicity to renal proximal tubules. Am J Physiol. 1990; 258(5 Pt 2):F1181-7. DOI: 10.1152/ajprenal.1990.258.5.F1181. View

14.

Terada Y, Inoshita S, Kuwana H, Kobayashi T, Okado T, Ichijo H . Important role of apoptosis signal-regulating kinase 1 in ischemic acute kidney injury. Biochem Biophys Res Commun. 2007; 364(4):1043-9. DOI: 10.1016/j.bbrc.2007.10.122. View

15.

Terada Y, Tomita K, Homma M, Nonoguchi H, Yang T, Yamada T . Sequential activation of Raf-1 kinase, mitogen-activated protein (MAP) kinase kinase, MAP kinase, and S6 kinase by hyperosmolality in renal cells. J Biol Chem. 1994; 269(49):31296-301. View

16.

Lau A . Apoptosis induced by cisplatin nephrotoxic injury. Kidney Int. 1999; 56(4):1295-8. DOI: 10.1046/j.1523-1755.1999.00687.x. View

17.

Nath K . Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues. Kidney Int. 2006; 70(3):432-43. DOI: 10.1038/sj.ki.5001565. View

18.

Ferris C, Jaffrey S, Sawa A, Takahashi M, Brady S, Barrow R . Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol. 1999; 1(3):152-7. DOI: 10.1038/11072. View

19.

Salahudeen A, Jenkins J, Huang H, Ndebele K, Salahudeen A . Overexpression of heme oxygenase protects renal tubular cells against cold storage injury: studies using hemin induction and HO-1 gene transfer. Transplantation. 2001; 72(9):1498-504. DOI: 10.1097/00007890-200111150-00005. View

20.

Nath K, Balla G, Vercellotti G, Balla J, JACOB H, Levitt M . Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest. 1992; 90(1):267-70. PMC: 443091. DOI: 10.1172/JCI115847. View