Implication of Lupeol in compensating Sorafenib-induced perturbations of redox homeostasis: A preclinical study in mouse model.

ABSTRACT

AIMS: Cancer chemotherapeutic drugs can potentially cause several adverse effects that influence a patient's general well-being. Sorafenib, an approved drug used in clinics against multiple cancers whose overall efficacy suffered a serious setback due to various side effects, leading to its frequent discontinuation. Lupeol has recently been considered an important prospective therapeutic agent due to its low toxicity and enhanced biological efficacy. Hence, our study aimed to evaluate whether Lupeol can perturb the Sorafenib-induced toxicity. MAIN METHODS: To test our hypothesis, we studied DNA interaction, level of cytokines, LFT/RFT, oxidant/antioxidant status, and their influences on genetic, cellular, and histopathological changes using both in vitro and in vivo models. KEY FINDINGS: The Sorafenib-treated group showed a marked increase in reactive oxygen and nitrogen species (ROS/RNS), an increase in liver and renal function marker enzymes, serum cytokines (IL-6, TNF-α, IL-1ß) macromolecular damages (protein, lipid, and DNA), and a decrease in antioxidant enzymes (SOD, CAT, TrxR, GPx, GST). Moreover, Sorafenib-induced oxidative stress caused marked cytoarchitectural damage in the liver and kidney and increased p53 and BAX expression. Interestingly, combining Lupeol with Sorafenib improves all the examined toxic insults caused by Sorafenib. In conclusion, our findings suggest that Lupeol can be used in combination with Sorafenib to reduce ROS/RNS-induced macromolecule damage, which might result in hepato-renal toxicity. SIGNIFICANCE: This study presents the possible protective effect of Lupeol against Sorafenib-induced adverse effects by perturbing redox homeostasis imbalance and apoptosis leading to tissue damage. This study is a fascinating finding that warrants further in-depth preclinical and clinical studies.