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Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells

Despite significant progress in the diagnosis and treatment of colorectal cancer, drug resistance continues to be a major limitation of therapy. In this regard, studies aimed at creating combination therapy are gaining popularity. One of the most promising adjuvants are inhibitors of the proteostasi...

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Autores principales: Nikotina, Alina D., Vladimirova, Snezhana A., Kokoreva, Nadezhda E., Komarova, Elena Y., Aksenov, Nikolay D., Efremov, Sergey, Leonova, Elizaveta, Pavlov, Rostislav, Kartsev, Viktor G., Zhang, Zhichao, Margulis, Boris A., Guzhova, Irina V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331496/
https://www.ncbi.nlm.nih.gov/pubmed/35893747
http://dx.doi.org/10.3390/ph15080923
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author Nikotina, Alina D.
Vladimirova, Snezhana A.
Kokoreva, Nadezhda E.
Komarova, Elena Y.
Aksenov, Nikolay D.
Efremov, Sergey
Leonova, Elizaveta
Pavlov, Rostislav
Kartsev, Viktor G.
Zhang, Zhichao
Margulis, Boris A.
Guzhova, Irina V.
author_facet Nikotina, Alina D.
Vladimirova, Snezhana A.
Kokoreva, Nadezhda E.
Komarova, Elena Y.
Aksenov, Nikolay D.
Efremov, Sergey
Leonova, Elizaveta
Pavlov, Rostislav
Kartsev, Viktor G.
Zhang, Zhichao
Margulis, Boris A.
Guzhova, Irina V.
author_sort Nikotina, Alina D.
collection PubMed
description Despite significant progress in the diagnosis and treatment of colorectal cancer, drug resistance continues to be a major limitation of therapy. In this regard, studies aimed at creating combination therapy are gaining popularity. One of the most promising adjuvants are inhibitors of the proteostasis system, chaperone machinery, and autophagy. The main HSP regulator, HSF1, is overactivated in cancer cells and autophagy sustains the survival of malignant cells. In this work, we focused on the selection of combination therapy for the treatment of rectal cancer cells obtained from patients after tumor biopsy without prior treatment. We characterized the migration, proliferation, and chaperone status in the resulting lines and also found them to be resistant to a number of drugs widely used in the clinic. However, these cells were sensitive to the autophagy inhibitor, chloroquine. For combination therapy, we used an HSF1 activity inhibitor discovered earlier in our laboratory, the cardenolide CL-43, which has already been proven as an auxiliary component of combined therapy in established cell lines. CL-43 effectively suppressed HSF1 activity and Hsp70 expression in all investigated cells. We tested the autophagy inhibitor, chloroquine, in combination with CL-43. Our results indicate that the use of an inhibitor of HSF1 activity in combination with an autophagy inhibitor results in effective cancer cell death, therefore, this therapeutic approach may be a promising treatment regimen for certain patients.
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spelling pubmed-93314962022-07-29 Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells Nikotina, Alina D. Vladimirova, Snezhana A. Kokoreva, Nadezhda E. Komarova, Elena Y. Aksenov, Nikolay D. Efremov, Sergey Leonova, Elizaveta Pavlov, Rostislav Kartsev, Viktor G. Zhang, Zhichao Margulis, Boris A. Guzhova, Irina V. Pharmaceuticals (Basel) Brief Report Despite significant progress in the diagnosis and treatment of colorectal cancer, drug resistance continues to be a major limitation of therapy. In this regard, studies aimed at creating combination therapy are gaining popularity. One of the most promising adjuvants are inhibitors of the proteostasis system, chaperone machinery, and autophagy. The main HSP regulator, HSF1, is overactivated in cancer cells and autophagy sustains the survival of malignant cells. In this work, we focused on the selection of combination therapy for the treatment of rectal cancer cells obtained from patients after tumor biopsy without prior treatment. We characterized the migration, proliferation, and chaperone status in the resulting lines and also found them to be resistant to a number of drugs widely used in the clinic. However, these cells were sensitive to the autophagy inhibitor, chloroquine. For combination therapy, we used an HSF1 activity inhibitor discovered earlier in our laboratory, the cardenolide CL-43, which has already been proven as an auxiliary component of combined therapy in established cell lines. CL-43 effectively suppressed HSF1 activity and Hsp70 expression in all investigated cells. We tested the autophagy inhibitor, chloroquine, in combination with CL-43. Our results indicate that the use of an inhibitor of HSF1 activity in combination with an autophagy inhibitor results in effective cancer cell death, therefore, this therapeutic approach may be a promising treatment regimen for certain patients. MDPI 2022-07-25 /pmc/articles/PMC9331496/ /pubmed/35893747 http://dx.doi.org/10.3390/ph15080923 Text en © 2022 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 Brief Report
Nikotina, Alina D.
Vladimirova, Snezhana A.
Kokoreva, Nadezhda E.
Komarova, Elena Y.
Aksenov, Nikolay D.
Efremov, Sergey
Leonova, Elizaveta
Pavlov, Rostislav
Kartsev, Viktor G.
Zhang, Zhichao
Margulis, Boris A.
Guzhova, Irina V.
Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells
title Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells
title_full Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells
title_fullStr Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells
title_full_unstemmed Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells
title_short Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells
title_sort combined cytotoxic effect of inhibitors of proteostasis on human colon cancer cells
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331496/
https://www.ncbi.nlm.nih.gov/pubmed/35893747
http://dx.doi.org/10.3390/ph15080923
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