Effect Of Rotundic Acid On Hepatocellular Carcinoma And Its Mechanism Of Action

According to the reports published by the International Association for Research on Cancer,hepatocellular carcinoma(HCC),overall is the sixth most common cancer in terms of incidence and is the fourth leading cause of cancer related deaths.When detected at an early stage,surgical resection,radiofrequency ablation,chemoembolization etc.are few possible treatments of choice for this highly malignant disorder.But if surgery is not an option,the spread of HCC can be controlled by targeted drug therapy.Since liver malignancies are usually detected at their advanced stages,the disease is very lethal and at these stages chemotherapy alone or in combination with other treatment modes remain the best possible ways to provide survival benefits in HCC.Over the last two decades,Sorafenib and Regorafenib have been the only chemical agents approved by the FDA for HCC treatment.Although these targeted agents have moderately improved the median survival period,they have failed to produce sustainable survival benefits.The limited therapeutic benefits and absence of durable response of the present-day chemotherapeutic agents calls for the urgent development of novel and contemporary curative agents with the aim of improving treatment response and minimizing toxicity for patients with HCC.The current study demonstrates the anti-cancer efficacy of rotundic acid(RA),a plant derived triterpenoid,on HCC under in vitro and in vivo conditions.MTT,cell migration,and invasion assays indicated that RA could successfully inhibit the cell viability,proliferation,and migratory potential of Hep G2,SMMC-7721,and endothelial HUVEC cells.Long-lasting effects of RA on HCC cell proliferation were established by the soft agar colony formation and clonogenic assays.Flow cytometry,confocal,and WB results further indicated that RA induced S-phase cell cycle arrest,DNA damage,and apoptosis by modulating the AKT/m TOR and MAPK pathway molecules.Tube formation and VEGF-ELISA revealed the anti-angiogenic abilities of RA on HCC.Furthermore,RA also inhibited Hep G2 tumor growth in Balb/c nude mouse model.To our best knowledge,this is the first extensive study of the anticancer activity of RA on HCC.Our results demonstrate that RA could be useful in treating aggressive malignant diseases and can be further developed as a chemo-preventive agent against human hepatocellular carcinoma.