Regulation of the PI3K/AKT/mTOR cascade in Hepatocellular Carcinoma Using Flavonoid Molecules

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the leading causes of global cancer death. The phosphatidylinositol-3-kinase/ protein kinase B/ mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is one of the highly regulated signalling transduction pathways in cells promoting cell survival, growth, motility, metabolism, and proliferation. This signalling axis is aberrantly activated in a wide variety of tumours, such as breast, cervical, colon, gastric, liver, lung, ovarian, and prostate. The PI3K/AKT/mTOR (PAM) signalling axis is the most pivotal and overactivated signalling pathway in ⁓50% of HCC cases. Phytochemicals, such as flavonoids, have been identified and isolated to date and are reported to have anticancer, cardioprotective, anti-inflammatory, anti-oxidant, and hepato-protective properties. METHODS: Studies discussed in this review were obtained from PubMed, Scopus, and Google Scholar databases using combinations of the terms related to HCC and flavonoids. RESULTS: This review summarizes the mechanism of action of flavonoids to get a better understanding of their role in HCC. It also discusses mechanistic approaches for targeting the PAM pathway using various flavonoid moieties. DISCUSSION: The scientific literature describes the pharmacological aspect of various flavonoids in targeting the "PAM axis" to manage hepatocarcinogenesis. These flavonoids chemo-sensitize the target, thus reducing the chance of resistance towards the chemotherapy, and also act as direct antioxidants, indirect antioxidants, or pro-oxidants. CONCLUSION: Further studies are required to investigate the pharmacokinetic profile of flavonoids as they hold immense potential to inhibit the PAM pathway in the management of hepatocellular carcinoma.