Therapeutic potential of natural triterpenoids in liver cancer

Pathologically, primary liver cancer is a heterogeneous, aggressive malignancy and encompasses hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and other rare tumors. This cancer remains the fifth most common malignancy in men and the eighth in women and the fourth leading cause of cancer-related mortality worldwide. Clinically, most liver cancer occurs typically from a background of cirrhosis and chronic inflammation. Liver cancer remains difficult to treat; small-molecule kinase inhibitors such as sorafenib and lenvatinib have only limited clinical benefit. Therefore, an urgent need exists to develop novel drugs for the treatment of liver cancer. Triterpenoids, consisting of six isoprene units, are structurally diverse secondary metabolites and possess versatile biological activities including immunomodulatory and antitumor activities. In this review, we discuss the therapeutic potential of natural triterpenoids in liver cancer, primarily focusing on their possible mechanisms involving induction of cell cycle arrest, initiation of apoptosis, activation of autophagy, stimulation of antitumor immune response, suppression of angiogenesis and metastasis, and enhancement of radio/chemo-sensitivity. We also present the current challenges that impede their translation to clinical practices. We conclude that natural triterpenoids could serve as potential candidates for developing liver cancer therapies, based on the current preclinical evidence. However, their clinical translation requires further validation. Hopefully, the knowledge gained from this review will outline future research directions and identify current research priorities in this field.