Hydroxytyrosol suppressed the nephrotoxicity of cisplatin while supporting its therapeutic potential in a rat model of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. The most important side effect of the chemotherapeutic agent Cisplatin (CIS) is nephrotoxicity. This study aimed to determine how Hydroxytyrosol (HxT), a potent antioxidant, affects the chemotherapeutic effect of CIS against Diethylnitrosamine (DENA)-induced HCC in liver tissue and its effectiveness on the damage caused by CIS in kidney tissues. In the experimental design, 56 male rats were divided into 8 groups (n = 7) for an 8-week experimental period. The rats were randomly assigned to one of the following groups: Control, HCC, HCC+HxT, HCC+CIS, CIS, CIS+HxT, HCC+CIS+HxT, and HxT, in equal numbers (n = 7). The effects of HxT in the HCC and/or CIS groups were examined using biochemical, histopathological, immunohistochemical, real-time PCR, and Western blot techniques. The study found increased liver and kidney function tests, histopathological changes, endoplasmic reticulum stress (ERS) markers, and inflammatory markers in the HCC and/or CIS groups compared to the control group. Furthermore, decreased levels of Phoenixin-14 (PNX-14), an endogenous polypeptide, were observed in the HCC and/or CIS groups compared to the control group. Significantly improved changes resulting from HCC and/or CIS were observed in the HxT-treated groups. Furthermore, cell culture analyses revealed that HxT exhibited cytotoxic effects against the HCC cell line. Conclusively, HxT supplementation demonstrated antioxidant, anti-inflammatory, and anti-apoptotic effects against CIS-induced nephrotoxicity. However, the combination of CIS and HxT may have a more effective anticancer effect against HCC rather than using them separately.