Combining Crocin and Sorafenib Improves Their Tumor-Inhibiting Effects in a Rat Model of Diethylnitrosamine-Induced Cirrhotic-Hepatocellular Carcinoma

SIMPLE SUMMARY: Liver cancer represents one of the most lethal forms of cancer, with hepatocellular carcinoma (HCC) accounting for the majority of its incidences and deaths. Currently, sorafenib is the first-in-line option for treating advanced and unresectable HCC. It is a multi-kinase inhibitor that intervenes with tumor growth and progression. Considering the modest results provided by sorafenib, identifying novel approaches to treating HCC remains a clinical imperative. Based on our previous work, crocin, a constituent of saffron, prevented HCC development. This study aimed to investigate its therapeutic effect in combination with sorafenib against an induced model of hepatocellular carcinoma arising from a cirrhotic milieu in rats. Our results confirmed that combination therapy yielded more effective outcomes compared to crocin and sorafenib monotherapies. It exerted the most pronounced effects in inhibiting inflammation and tumor cell proliferation while activating apoptosis and restoring macroscopic and cellular liver morphology. These results introduce a potential strategy for optimizing the anticancer effects of sorafenib using the bioactive natural compound crocin against HCC. ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies, with continuously increasing cases and fatalities. Diagnosis often occurs in the advanced stages, confining patients to systemic therapies such as sorafenib. Sorafenib (SB), a multi-kinase inhibitor, has not yet demonstrated sufficient efficacy against advanced HCC. There is a strong argument in favor of studying its use in combination with other medications to optimize the therapeutic results. According to our earlier work, crocin (CR), a key bioactive component of saffron, hinders HCC development and liver cancer stemness. In this study, we investigated the therapeutic use of CR or its combination with SB in a cirrhotic rat model of HCC and evaluated how effectively SB and CR inhibited tumor growth in this model. Diethylnitrosamine (DEN) was administered intraperitoneally to rats once a week for 15 weeks, leading to cirrhosis, and then 19 weeks later, leading to multifocal HCC. After 16 weeks of cancer induction, CR (200 mg/kg daily) and SB (10 mg/kg daily) were given orally to rats for three weeks, either separately or in combination. Consistently, the combination treatment considerably decreased the incidence of dyschromatic nodules, nodule multiplicity, and dysplastic nodules when compared to the HCC group of single therapies. Combined therapy also caused the highest degree of apoptosis, along with decreased proliferating and β-catenin levels in the tumor tissues. Additionally, when rats received combined therapy with CR, it showed anti-inflammatory characteristics where nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (Cox-2) were considerably and additively lowered. As a result, CR potentiates the suppressive effects of SB on tumor growth and provides the opportunity to strengthen the therapeutic effects of SB in the treatment of HCC.