Repurposing PDE5 inhibitor tadalafil and sildenafil as anticancer agent against hepatocellular carcinoma via targeting key events of glucose metabolism and multidrug resistance.

Abstract

Hepatocellular carcinoma (HCC) has emerged asone of the most common and lethal cancers worldwide and is caused due to contamination of diets with aflatoxin B1 and chronic viral hepatitis. Recent reports suggest that phosphodiesterase-5 inhibitor (PDE5i) exhibits anticancer properties against several forms of cancer but till now has not been evaluated against HCC. We aimed to evaluate the anticancer property of phosphodiesterase-5 inhibitors (PDE5i) tadalafil and sildenafil against aflatoxin B1 HCC. Rats of HCC group were fed with 5% alcohol via drinking water for 3 weeks, followed by administration of AFB1 (1 mg/kg/bw, i.p.) at an interval of two subsequent days. PDE5i (tadalafil and sildenafil, 10 mg/kg bw) was administered along with drinking water after 6 weeks of treatment with AFB1 for 2 weeks. In the present investigation, in HCC elevation in the level of SGOT, SGPT, ALP, and urea vis-à-vis activity of key glycolytic enzyme LDH and mRNA expression of c-myc, Akt, LDH-A, and PFKFB3 was noted. Similarly, the level of multidrug resistance protein (MDR) and breast cancer resistance protein (BCRP/ABCG2) was elevated along with increased expression of angiogenesis marker (HIF-1α, VEGF, andTGF-β1) in HCC. Post-treatment with PDE5 inhibitor (tadalafil and sildenafil) downregulated and brought back the above parameters towards normal and out of two PDE5i (tadalafil and sildenafil), sildenafil effect was more potent as compared to tadalafil. Our findings demonstrate for the first time that PDE5 inhibitors tadalafil and sildenafil are able to prohibit the development and progression of aflatoxin B1 induced HCC.