Repurposing PDE5 inhibitor tadalafil and sildenafil as anticancer agent against hepatocellular carcinoma via targeting key events of glucose metabolism and multidrug resistance. Issue 8 (24th May 2022) - Chhonker, Saurabh Kumar
Abstract: Hepatocellular carcinoma (HCC) has emerged as one 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, and TGF‐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. Highlights: PDE5 inhibitor tadalafil and sildenafil may play an important role in the regulation of blood glucose and glycolytic parameter while exhibiting anticancer activity in hepatocellular carcinoma (HCC) rats. Overexpression of MDR1 and BCRP can promote multidrug resistance phenotype in cancer cells and thus can negatively affect the efficacy of chemotherapeutic agents. The ability of PDE5 inhibitor to decline the expression of MDR1 and BCRP is important from clinical perspective; like outcomes of chemotherapy when used synergistically. There is no previous report examining the PDE5 inhibitors in vivo in alcohol—aflatoxin B1 induced HCC and the outcome of the present findings has a great impact on understanding the aflatoxin B1 associated outcome in populations where consumption of aflatoxin‐contaminated food is quite common. Abstract : Protective role of PDE5 inhibitor tadalafil and sildenafil in aflatoxin B1 induced hepatocellular carcinoma (HCC).