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Hepatobiliary Cancers: Pathobiology and Translational Advances | EK29


Uttroside B as a novel drug candidate against Hepatocellular Carcinoma


Mar 22, 2021 12:00am ‐ Mar 22, 2021 12:00am

Description

Uttroside B as a novel drug candidate against Hepatocellular Carcinoma Uttroside B as a novel drug candidate against Hepatocellular Carcinoma Swetha. M1, Lekshmi R. Nath1, Ravi S Lankalappally2 Ruby John Anto 1* 1 Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram-695014, Kerala, India, e-mail: swetham@rgcb.res.in; 2Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram-695019, Kerala, India;*corresponding author OBJECTIVE Hepatocellular carcinoma (HCC) is associated with a high rate of mortality and exhibits inherent resistance to conventional chemotherapeutics. Our team has isolated a furostanol saponin, uttroside B, from the leaves of Solanum nigrum Linn, which exhibits exceptional cytotoxicity towards liver cancer cells, compared to sorafenib, the only FDA approved drug against HCC. The present study aimed to evaluate the chemotherapeutic potential of uttroside B. METHODS Solvent extraction of Solanum nigrum Linn leaves; MTT assay, Western blotting, EMSA, histopathology, immunohistochemistry, Anti-tumor studies in NOD-SCID mice; Toxicological studies in Swiss albino mice, Carcinogenesis studies in DBA/2J mice, Hemolysis, Transfection. RESULTS Previous studies conducted in our lab have shown that uttroside B, a potent saponin isolated and characterized from the leaves of Solanum nigrum Linn shows exceptional cytotoxicity towards liver cancer cell lines, irrespective of their HBV status, while being non-toxic to normal immortalized hepatocytes. It has been found that Uttroside B is more than ten times cytotoxic to liver cancer cell line, HepG2 (IC50: 0.5 μM) than sorafenib (IC50: 5.8 μM), the only FDA approved drug against HCC. Uttroside B drastically inhibited the growth of HepG2 liver cancer xenografts in NOD-SCID mice and also exhibits better anti-tumor efficacy than sorafenib as indicated by our in vivo studies. Unlike other saponins, uttroside B did not induce hemolysis. It induces vacuolated structures indicative of autophagy and activates autophagy markers such as LC3 II, Beclin 1&Atg proteins. Uttroside B-induced autophagy flux was confirmed using bafilomycin A1 and quantitated by RFP-GFP-LC3-tagged protein assay. Inhibition of autophagy by Bafilomycin A1, 3-MA, beclin siRNA transfection and chloroquine enhanced the uttroside B-mediated apoptosis. Increased presence of autophagic markers in tumor xenografts of mice treated with Uttroside B strongly indicates that the inhibition of autophagy can be exploited as a future clinical strategy to avoid the possible chemotherapeutic resistance of uttroside B treatment. A synergistic combination of Chloroquine (10µM) with Uttroside B (250 nM) significantly reduced the viability of HepG2 cells in vitro and xenograft studies of this combination significantly reduced the tumor volume. Of the 550,000–600,000 new HCC cases worldwide each year, about 25,200–155,000 may be attributable to aflatoxin exposure. Aflatoxins have been classified as Group 1 human carcinogen by IARC. We have successfully established aflatoxin-induced carcinogenesis model using DBA/2J mice. Uttroside B treatment significantly inhibited the tumor growth in the carcinogenesis model. Administration of uttroside B contained in the leaves of Solanum nigrum Linn is currently going on patients of naturopathy treatment against liver disorders indicates its safety as assessed by their liver and kidney function parameters. A patent has been granted on the anti-cancer potential of Uttroside B (National Patent Application No. 201641018401 dated 28th May 2016, US patent Application No. PCT/ IN20 17/050204 dated 27th May 2017). CONCLUSION The study attests uttroside B as a promising drug candidate against HCC. Key words: Uttroside B; HCC; Autophagy; mTOR; AMPK Acknowledgments: UGC for fellowship. Presenting author: Swetha. M, E-mail: swetham@rgcb.res.in, Tel.: +91 9744393976

Speaker(s):

  • Swetha M, MSc, Rajiv Gandhi Centre for Biotechnology (RGCB)

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