Protective Mechanisms of Limonoids from Khaya grandifoliola against Cisplatin-Toxicity in L-02 Hepatocytes: Targeting JNK Activation and Nuclear Translocation of Nrf2 – Investigational Medicinal Chemistry and Pharmacology

Abstract

Background: Cisplatin is one of the most effective antineoplastic drugs, but it has undesirable side effects such as hepatotoxicity. This study investigated in vitro the protective activity of three limonoids known as 17-epi-methyl-6-hydroxylangolensate, 7-deacetoxy-7-oxogedunin and deacetoxy-7R-hydroxygedunin, isolated from Khaya grandifoliola (Meliaceae) against cisplatin-induced hepatotoxicity and the possible mechanisms involved in this activity.

Methods: Normal human liver L-02 cells line were intoxicated with cisplatin or co-treated with the limonoids for 36h prior to evaluation of biochemical and molecular parameters through spectrophotometric assays, western blots and quantitative real-time polymerase chain reaction analysis.

Results: The studied limonoids prevented cisplatin-induced cell death and leakage of alanine aminotransferase (ALT) in the incubation medium in a concentration-dependent manner. Overproduction of intracellular reactive oxygen species (ROS), depletion of glutathione and lipid membrane peroxidation induced by cisplatin were inhibited by the limonoids. Cisplatin-induced phosphorylation of c-Jun N-terminal Kinase (JNK) and mitochondrial translocation of phospho-JNK was abrogated in limonoids co-treated cells. Interestingly, the studied limonoids increased the expression of mitogen-activated protein kinase phosphatase -1, an endogenous inhibitor of JNK phosphorylation, in cisplatin-intoxicated cells. Moreover, these compounds induced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), decreased the expression of kelch-like ECH-associated protein-1, and increased the mRNA levels of Nrf2 target genes: catalase, superoxide dismutase-1 and glutathione-S-transferase.

Conclusions: The present findings suggest that limonoids from K. grandifoliola may constitute promising phytochemicals for alleviating cisplatin-induced hepatotoxicity.

Key words: Khaya grandifoliola; Limonoids; Cisplatin-toxicity; hepato-protection.

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