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Inducing Cytotoxicity in Colon Cancer Cells and Suppressing Cancer Stem Cells by Dolasetron and Ketoprofen through Inhibition of RNA Binding Protein PUM1

Clinical trials of new drugs often face a high failure rate of approximately 45 percent due to safety and toxicity concerns. Repurposing drugs with well-established safety profiles becomes crucial in addressing this challenge. Colon cancer ranks as the third most prevalent cancer and the second lead...

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Autores principales: Gor, Ravi, Gharib, Ali, Dharshini Balaji, Priya, Madhavan, Thirumurthy, Ramalingam, Satish
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10458631/
https://www.ncbi.nlm.nih.gov/pubmed/37624174
http://dx.doi.org/10.3390/toxics11080669
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author Gor, Ravi
Gharib, Ali
Dharshini Balaji, Priya
Madhavan, Thirumurthy
Ramalingam, Satish
author_facet Gor, Ravi
Gharib, Ali
Dharshini Balaji, Priya
Madhavan, Thirumurthy
Ramalingam, Satish
author_sort Gor, Ravi
collection PubMed
description Clinical trials of new drugs often face a high failure rate of approximately 45 percent due to safety and toxicity concerns. Repurposing drugs with well-established safety profiles becomes crucial in addressing this challenge. Colon cancer ranks as the third most prevalent cancer and the second leading cause of cancer related mortality worldwide. This study focuses on the RNA-binding protein pumilio1 (PUM1), a member of the PUF family involved in post-transcriptional gene expression regulation. By utilizing molecular docking techniques and FDA-approved drugs, potential inhibitors against PUM1 were identified. Notably, dolasetron and ketoprofen demonstrated promising results, exhibiting strong binding affinity, hydrophobic interactions, and favorable chemical reactivity according to Conceptual-DFT calculations. Both compounds effectively reduced cell viability, with IC50 values of 150 µM and 175 µM, respectively and shows long term inhibitory effects as seen by reduced in number of colonies. Moreover, they exhibited inhibitory effects on colon cancer stem cells, as indicated by reduced colonospheroid size and numbers. Apoptosis is induced by these compounds and has triggered activation of executioner caspase 3/7 in HCT116 cells which is evident through a caspase 3/7 assay and AO/EB staining, while the non-toxic effect of these compounds was evident from viability against non-cancerous cell line and hemolysis assay. Additionally, the treatment group showed a significant decrease in PUM1 and cancer stem cell markers expression compared to the control group. In conclusion, this study highlights the potential of targeting PUM1 as a novel approach to colon cancer treatment. Dolasetron and ketoprofen demonstrate promise as effective anti-cancer and anti-cancer stem cell drugs, inducing apoptosis in colon cancer cells through inhibition of PUM1.
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spelling pubmed-104586312023-08-27 Inducing Cytotoxicity in Colon Cancer Cells and Suppressing Cancer Stem Cells by Dolasetron and Ketoprofen through Inhibition of RNA Binding Protein PUM1 Gor, Ravi Gharib, Ali Dharshini Balaji, Priya Madhavan, Thirumurthy Ramalingam, Satish Toxics Article Clinical trials of new drugs often face a high failure rate of approximately 45 percent due to safety and toxicity concerns. Repurposing drugs with well-established safety profiles becomes crucial in addressing this challenge. Colon cancer ranks as the third most prevalent cancer and the second leading cause of cancer related mortality worldwide. This study focuses on the RNA-binding protein pumilio1 (PUM1), a member of the PUF family involved in post-transcriptional gene expression regulation. By utilizing molecular docking techniques and FDA-approved drugs, potential inhibitors against PUM1 were identified. Notably, dolasetron and ketoprofen demonstrated promising results, exhibiting strong binding affinity, hydrophobic interactions, and favorable chemical reactivity according to Conceptual-DFT calculations. Both compounds effectively reduced cell viability, with IC50 values of 150 µM and 175 µM, respectively and shows long term inhibitory effects as seen by reduced in number of colonies. Moreover, they exhibited inhibitory effects on colon cancer stem cells, as indicated by reduced colonospheroid size and numbers. Apoptosis is induced by these compounds and has triggered activation of executioner caspase 3/7 in HCT116 cells which is evident through a caspase 3/7 assay and AO/EB staining, while the non-toxic effect of these compounds was evident from viability against non-cancerous cell line and hemolysis assay. Additionally, the treatment group showed a significant decrease in PUM1 and cancer stem cell markers expression compared to the control group. In conclusion, this study highlights the potential of targeting PUM1 as a novel approach to colon cancer treatment. Dolasetron and ketoprofen demonstrate promise as effective anti-cancer and anti-cancer stem cell drugs, inducing apoptosis in colon cancer cells through inhibition of PUM1. MDPI 2023-08-03 /pmc/articles/PMC10458631/ /pubmed/37624174 http://dx.doi.org/10.3390/toxics11080669 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gor, Ravi
Gharib, Ali
Dharshini Balaji, Priya
Madhavan, Thirumurthy
Ramalingam, Satish
Inducing Cytotoxicity in Colon Cancer Cells and Suppressing Cancer Stem Cells by Dolasetron and Ketoprofen through Inhibition of RNA Binding Protein PUM1
title Inducing Cytotoxicity in Colon Cancer Cells and Suppressing Cancer Stem Cells by Dolasetron and Ketoprofen through Inhibition of RNA Binding Protein PUM1
title_full Inducing Cytotoxicity in Colon Cancer Cells and Suppressing Cancer Stem Cells by Dolasetron and Ketoprofen through Inhibition of RNA Binding Protein PUM1
title_fullStr Inducing Cytotoxicity in Colon Cancer Cells and Suppressing Cancer Stem Cells by Dolasetron and Ketoprofen through Inhibition of RNA Binding Protein PUM1
title_full_unstemmed Inducing Cytotoxicity in Colon Cancer Cells and Suppressing Cancer Stem Cells by Dolasetron and Ketoprofen through Inhibition of RNA Binding Protein PUM1
title_short Inducing Cytotoxicity in Colon Cancer Cells and Suppressing Cancer Stem Cells by Dolasetron and Ketoprofen through Inhibition of RNA Binding Protein PUM1
title_sort inducing cytotoxicity in colon cancer cells and suppressing cancer stem cells by dolasetron and ketoprofen through inhibition of rna binding protein pum1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10458631/
https://www.ncbi.nlm.nih.gov/pubmed/37624174
http://dx.doi.org/10.3390/toxics11080669
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