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Protective and therapeutic effects of sildenafil and tadalafil on aflatoxin B1-induced hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC) has been classified as one of the most common forms of liver cancer occurring worldwide, and risk factors include hepatitis B & C virus, alcoholism, and dietary carcinogens like aflatoxin B1 (AFB1), which is produced by fungus Aspergillus flavus and Aspergillus parasiticus. Metabolism of AFB1 resulted into the formation of AFB1-exo-8, 9-epoxide which is largely responsible for HCC development. So far conventional cytotoxic chemotherapy has not provided much benefit in HCC, necessitating the need for newer treatment modalities. Recent reports suggest that phosphodiesterase-5 inhibitors (PDE5i) may have anticancer activity, but till date, the anticancer property of PDE5i (tadalafil & sildenafil) has not been evaluated in HCC. The present study was aimed to define the anticancer property of tadalafil and sildenafil against AFB1-induced HCC rats. Rats were randomly divided into five groups with five rats in each group. Except normal control group, rats of all other groups were fed with 5% alcohol via drinking water for 3 weeks. After 3 weeks, two successive dose of AFB1 (1 mg/kg bw, ip) was administered on subsequent days followed by the administration of PDE5i (tadalafil & sildenafil, 10 mg/kg bw) along with drinking water after 6 weeks of treatment with AFB1 for 2 weeks. An in-depth investigation into its mechanistic aspect revealed that development of HCC induced by aflatoxin B1, decreased the mRNA expression and activity of antioxidant enzyme SOD, GPx, catalase, GR and GST, and GSH content with a concomitant increase in the level of lipid peroxidation. Post-treatment with PDE5 inhibitor (tadalafil & sildenafil) restored the above parameters towards normal, and this result was more effective in case of sildenafil. Thus, results from the above studies suggest that PDE5 inhibitors may act as anticancer agents by preventing the development and progression of HCC by modulating the key parameters of antioxidant pathway.

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Abbreviations

AFB1:

Aflatoxin B1

AFP:

Alpha-fetoprotein

cAMP:

Cyclic adenosine monophosphate

cGMP:

Cyclic guanosine monophosphate

GPx:

Glutathione peroxide

GST-pi:

Placental form of glutathione S-transferase

HCC:

Hepatocellular carcinoma

PDE5i:

Phosphodiesterase-5 inhibitor

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

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Acknowledgements

SKC and DR are grateful to Dr. Harisingh Gour Vishwavidyalaya, Sagar, for fellowship. This work was financially supported by a project from UGC-Faculty Research Promotion Scheme (F.30-12/2014/BSR) and SERB (SERB/LS-816/2013), Govt. of India, sanctioned to RKK. The authors are thankful to Department of Zoology, Dr. Harisingh Gour Vishwavidyalaya, Sagar, for providing infrastructural facilities and financial support.

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  1. Biochemistry Laboratory, Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, 470003, India

    Saurabh K. Chhonker, Divya Rawat & Raj Kumar Koiri

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Chhonker, S.K., Rawat, D. & Koiri, R.K. Protective and therapeutic effects of sildenafil and tadalafil on aflatoxin B1-induced hepatocellular carcinoma. Mol Cell Biochem 476, 1195–1209 (2021). https://doi.org/10.1007/s11010-020-03982-6

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