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9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells

Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new ta...

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Autores principales: Poloznikov, Andrey, Nikulin, Sergey, Bolotina, Larisa, Kachmazov, Andrei, Raigorodskaya, Maria, Kudryavtseva, Anna, Bakhtogarimov, Ildar, Rodin, Sergey, Gaisina, Irina, Topchiy, Maxim, Asachenko, Andrey, Novosad, Victor, Tonevitsky, Alexander, Alekseev, Boris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8696016/
https://www.ncbi.nlm.nih.gov/pubmed/34955846
http://dx.doi.org/10.3389/fphar.2021.777114
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author Poloznikov, Andrey
Nikulin, Sergey
Bolotina, Larisa
Kachmazov, Andrei
Raigorodskaya, Maria
Kudryavtseva, Anna
Bakhtogarimov, Ildar
Rodin, Sergey
Gaisina, Irina
Topchiy, Maxim
Asachenko, Andrey
Novosad, Victor
Tonevitsky, Alexander
Alekseev, Boris
author_facet Poloznikov, Andrey
Nikulin, Sergey
Bolotina, Larisa
Kachmazov, Andrei
Raigorodskaya, Maria
Kudryavtseva, Anna
Bakhtogarimov, Ildar
Rodin, Sergey
Gaisina, Irina
Topchiy, Maxim
Asachenko, Andrey
Novosad, Victor
Tonevitsky, Alexander
Alekseev, Boris
author_sort Poloznikov, Andrey
collection PubMed
description Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.
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spelling pubmed-86960162021-12-24 9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells Poloznikov, Andrey Nikulin, Sergey Bolotina, Larisa Kachmazov, Andrei Raigorodskaya, Maria Kudryavtseva, Anna Bakhtogarimov, Ildar Rodin, Sergey Gaisina, Irina Topchiy, Maxim Asachenko, Andrey Novosad, Victor Tonevitsky, Alexander Alekseev, Boris Front Pharmacol Pharmacology Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC. Frontiers Media S.A. 2021-12-09 /pmc/articles/PMC8696016/ /pubmed/34955846 http://dx.doi.org/10.3389/fphar.2021.777114 Text en Copyright © 2021 Poloznikov, Nikulin, Bolotina, Kachmazov, Raigorodskaya, Kudryavtseva, Bakhtogarimov, Rodin, Gaisina, Topchiy, Asachenko, Novosad, Tonevitsky and Alekseev. 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 Pharmacology
Poloznikov, Andrey
Nikulin, Sergey
Bolotina, Larisa
Kachmazov, Andrei
Raigorodskaya, Maria
Kudryavtseva, Anna
Bakhtogarimov, Ildar
Rodin, Sergey
Gaisina, Irina
Topchiy, Maxim
Asachenko, Andrey
Novosad, Victor
Tonevitsky, Alexander
Alekseev, Boris
9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells
title 9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells
title_full 9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells
title_fullStr 9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells
title_full_unstemmed 9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells
title_short 9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells
title_sort 9-ing-41, a small molecule inhibitor of gsk-3β, potentiates the effects of chemotherapy on colorectal cancer cells
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8696016/
https://www.ncbi.nlm.nih.gov/pubmed/34955846
http://dx.doi.org/10.3389/fphar.2021.777114
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