Isorhamnetin exerts anti-tumor activity in DEN + CCl₄-induced HCC mice

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and the main cause of cancer death globally. The use of medicinal herbs as chemotherapeutic agents in cancer treatment is receiving attention as they possess no or minimum side effects. Isorhamnetin (IRN), a flavonoid, has been under attention for its anti-inflammatory and anti-proliferative properties in a number of cancers, including colorectal, skin, and lung cancers. However, the in vivo mechanism of isorhamnetin to suppress liver cancer has yet to be explored.

HCC was induced by N-diethylnitrosamine (DEN) and carbon tetrachloride (CCL₄) in Swiss albino mice. Isorhamnetin (100 mg/kg body weight) was given to examine its anti-tumor properties in HCC mice model. Histological analysis and liver function assays were performed to assess changes in liver anatomy. Probable molecular pathways were explored using immunoblot, qPCR, ELISA, and immunohistochemistry techniques. Isorhamnetin inhibited various pro-inflammatory cytokines to suppress cancer-inducing inflammation. Additionally, it regulated Akt and MAPKs to suppress Nrf2 signaling. Isorhamnetin activated PPAR-γ and autophagy while suppressing cell cycle progression in DEN + CCl₄-administered mice. Additionally, isorhamnetin regulated various signaling pathways to suppress cell proliferation, metabolism, and epithelial-mesenchymal transition in HCC.

Regulating diverse cellular signaling pathways makes isorhamnetin a better anti-cancer chemotherapeutic candidate in HCC. Importantly, the anti-TNF-α properties of isorhamnetin could prove it a valuable therapeutic agent in sorafenib-resistant HCC patients. Additionally, anti-TGF-β properties of isorhamnetin could be utilized to reduce the EMT-inducing side effects of doxorubicin.