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Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma

Our previous study has demonstrated that Uttroside B (Utt-B), a saponin isolated from the leaves of Solanum nigrum Linn induces apoptosis in hepatic cancer cells and exhibits a remarkable growth inhibition of Hepatocellular Carcinoma (HCC). Our innovation has been granted a patent from the US (US 20...

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Autores principales: Nath, Lekshmi R., Swetha, Mundanattu, Vijayakurup, Vinod, Thangarasu, Arun Kumar, Haritha, Nair Hariprasad, Shabna, Anwar, Aiswarya, Sreekumar U., Rayginia, Tennyson P., Keerthana, C. K., Kalimuthu, Kalishwaralal, Sundaram, Sankar, Lankalapalli, Ravi Shankar, Pillai, Sreekumar, Towner, Rheal, Isakov, Noah, Anto, Ruby John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861526/
https://www.ncbi.nlm.nih.gov/pubmed/35211405
http://dx.doi.org/10.3389/fonc.2022.812598
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author Nath, Lekshmi R.
Swetha, Mundanattu
Vijayakurup, Vinod
Thangarasu, Arun Kumar
Haritha, Nair Hariprasad
Shabna, Anwar
Aiswarya, Sreekumar U.
Rayginia, Tennyson P.
Keerthana, C. K.
Kalimuthu, Kalishwaralal
Sundaram, Sankar
Lankalapalli, Ravi Shankar
Pillai, Sreekumar
Towner, Rheal
Isakov, Noah
Anto, Ruby John
author_facet Nath, Lekshmi R.
Swetha, Mundanattu
Vijayakurup, Vinod
Thangarasu, Arun Kumar
Haritha, Nair Hariprasad
Shabna, Anwar
Aiswarya, Sreekumar U.
Rayginia, Tennyson P.
Keerthana, C. K.
Kalimuthu, Kalishwaralal
Sundaram, Sankar
Lankalapalli, Ravi Shankar
Pillai, Sreekumar
Towner, Rheal
Isakov, Noah
Anto, Ruby John
author_sort Nath, Lekshmi R.
collection PubMed
description Our previous study has demonstrated that Uttroside B (Utt-B), a saponin isolated from the leaves of Solanum nigrum Linn induces apoptosis in hepatic cancer cells and exhibits a remarkable growth inhibition of Hepatocellular Carcinoma (HCC). Our innovation has been granted a patent from the US (US 2019/0160088A1), Canada (3,026,426.), Japan (JP2019520425) and South Korea (KR1020190008323) and the technology have been transferred commercially to Q Biomed, a leading US-based Biotech company. Recently, the compound received approval as ‘Orphan Drug’ against HCC from US FDA, which reveals the clinical relevance of evaluating its antitumor efficacy against HCC. In the present study, we report that Utt-B promotes pro-survival autophagy in hepatic cancer cells as evidenced by the increased expression of autophagy-related proteins, including LC3-II, Beclin1, ATG 5, and ATG 7, as well as a rise in the autophagic flux. Hence, we investigated whether Utt-B-induced autophagic response is complementing or contradicting its apoptotic program in HCC. Inhibition of autophagy using the pharmacological inhibitors, Bafilomycin A1(Baf A1), and 3-methyl adenine (3-MA), and the biological inhibitor, Beclin1 siRNA, significantly enhances the apoptosis of hepatic cancer cells and hence the cytotoxicity induced by Utt-B. We also found increased expression of autophagy markers in Utt-B-treated xenografts derived from HCC. We further analyzed whether the antimalarial drug, Chloroquine (Cqn), a well-known autophagy inhibitor, can enhance the anticancer effect of Utt-B against HCC. We found that inhibition of autophagy using Cqn significantly enhances the antitumor efficacy of Utt-B in vitro and in vivo, in NOD SCID mice bearing HCC xenografts. Taken together, our results suggest that the antitumor effect of Utt-B against HCC can be further enhanced by blocking autophagy. Furthermore, Utt-B in combination with Cqn, a clinically approved drug, if repurposed and used in a combinatorial regimen with Utt-B, can further improve the therapeutic efficacy of Utt-B against HCC.
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spelling pubmed-88615262022-02-23 Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma Nath, Lekshmi R. Swetha, Mundanattu Vijayakurup, Vinod Thangarasu, Arun Kumar Haritha, Nair Hariprasad Shabna, Anwar Aiswarya, Sreekumar U. Rayginia, Tennyson P. Keerthana, C. K. Kalimuthu, Kalishwaralal Sundaram, Sankar Lankalapalli, Ravi Shankar Pillai, Sreekumar Towner, Rheal Isakov, Noah Anto, Ruby John Front Oncol Oncology Our previous study has demonstrated that Uttroside B (Utt-B), a saponin isolated from the leaves of Solanum nigrum Linn induces apoptosis in hepatic cancer cells and exhibits a remarkable growth inhibition of Hepatocellular Carcinoma (HCC). Our innovation has been granted a patent from the US (US 2019/0160088A1), Canada (3,026,426.), Japan (JP2019520425) and South Korea (KR1020190008323) and the technology have been transferred commercially to Q Biomed, a leading US-based Biotech company. Recently, the compound received approval as ‘Orphan Drug’ against HCC from US FDA, which reveals the clinical relevance of evaluating its antitumor efficacy against HCC. In the present study, we report that Utt-B promotes pro-survival autophagy in hepatic cancer cells as evidenced by the increased expression of autophagy-related proteins, including LC3-II, Beclin1, ATG 5, and ATG 7, as well as a rise in the autophagic flux. Hence, we investigated whether Utt-B-induced autophagic response is complementing or contradicting its apoptotic program in HCC. Inhibition of autophagy using the pharmacological inhibitors, Bafilomycin A1(Baf A1), and 3-methyl adenine (3-MA), and the biological inhibitor, Beclin1 siRNA, significantly enhances the apoptosis of hepatic cancer cells and hence the cytotoxicity induced by Utt-B. We also found increased expression of autophagy markers in Utt-B-treated xenografts derived from HCC. We further analyzed whether the antimalarial drug, Chloroquine (Cqn), a well-known autophagy inhibitor, can enhance the anticancer effect of Utt-B against HCC. We found that inhibition of autophagy using Cqn significantly enhances the antitumor efficacy of Utt-B in vitro and in vivo, in NOD SCID mice bearing HCC xenografts. Taken together, our results suggest that the antitumor effect of Utt-B against HCC can be further enhanced by blocking autophagy. Furthermore, Utt-B in combination with Cqn, a clinically approved drug, if repurposed and used in a combinatorial regimen with Utt-B, can further improve the therapeutic efficacy of Utt-B against HCC. Frontiers Media S.A. 2022-02-08 /pmc/articles/PMC8861526/ /pubmed/35211405 http://dx.doi.org/10.3389/fonc.2022.812598 Text en Copyright © 2022 Nath, Swetha, Vijayakurup, Thangarasu, Haritha, Shabna, Aiswarya, Rayginia, Keerthana, Kalimuthu, Sundaram, Lankalapalli, Pillai, Towner, Isakov and Anto https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Nath, Lekshmi R.
Swetha, Mundanattu
Vijayakurup, Vinod
Thangarasu, Arun Kumar
Haritha, Nair Hariprasad
Shabna, Anwar
Aiswarya, Sreekumar U.
Rayginia, Tennyson P.
Keerthana, C. K.
Kalimuthu, Kalishwaralal
Sundaram, Sankar
Lankalapalli, Ravi Shankar
Pillai, Sreekumar
Towner, Rheal
Isakov, Noah
Anto, Ruby John
Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma
title Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma
title_full Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma
title_fullStr Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma
title_full_unstemmed Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma
title_short Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma
title_sort blockade of uttroside b-induced autophagic pro-survival signals augments its chemotherapeutic efficacy against hepatocellular carcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861526/
https://www.ncbi.nlm.nih.gov/pubmed/35211405
http://dx.doi.org/10.3389/fonc.2022.812598
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