ROSMARINIC ACID ENHANCES CISPLATIN CYTOTOXICITY IN HEPG2 CELL LINE AND ATTENUATES ITS NEPHROTOXICITY IN MICE

The present study aimed to investigate the anticancer effect of rosmarinic acid (RA), both alone and in combination with cisplatin (cis). Also, the potential nephroprotective effects of RA against cis-induced nephrotoxicity in mice and the possible mechanisms underlying this protection were explored. Treatment of HepG2 cells with RA produced a significant decline in cellular proliferation. RA induced cell cycle arrest at G₀ / G₁ phase and S phase, significantly inhibited vascular endothelial growth factor (VEGF) concentration and induced caspase-3 level in cell lysate. While pre-treatment with IC₅₀ RA before cis addition significantly enhanced cis cytotoxic activity in HepG2 cells. Moreover, Pre-treatment with RA significantly mitigated cis-induced elevation of blood urea nitrogen (BUN) and serum creatinine levels. The elevated levels of malondialdehyde (MDA), tumor necrosis factor- alpha (TNF-α), Bax and caspase-9 in kidney tissues were significantly reversed. Additionally, RA significantly abrogated cis-induced reduction in reduced glutathione level (GSH). The histopathological examination emphasized the obtained results. Conclusion: RA possesses cytotoxic activity against HepG2 cell line through cell cycle arrest, induction of caspase-3 and inhibition of VEGF. In addition, RA enhances cis-induced cytotoxicity in HepG2 cells. Also, it ameliorates cis-induced nephro-toxicity in mice; an effect which could be attributed to inhibition of oxidative stress, inflammation and apoptosis.