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Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells
Advanced colorectal cancer has a poor prognosis because of metastasis formation and resistance to combined therapies. Downstream of PI3K/Akt and Ras/MAPK pathways, the mTOR kinase plays a decisive role in treatment failure. We previously established that irinotecan has antiangiogenic properties and...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826690/ https://www.ncbi.nlm.nih.gov/pubmed/31627299 http://dx.doi.org/10.3390/cancers11101581 |
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author | Reita, Damien Bour, Cyril Benbrika, Radhia Groh, Audrey Pencreach, Erwan Guérin, Eric Guenot, Dominique |
author_facet | Reita, Damien Bour, Cyril Benbrika, Radhia Groh, Audrey Pencreach, Erwan Guérin, Eric Guenot, Dominique |
author_sort | Reita, Damien |
collection | PubMed |
description | Advanced colorectal cancer has a poor prognosis because of metastasis formation and resistance to combined therapies. Downstream of PI3K/Akt and Ras/MAPK pathways, the mTOR kinase plays a decisive role in treatment failure. We previously established that irinotecan has antiangiogenic properties and it is known that new mammalian target of rapamycin (mTOR) catalytic AZD inhibitors, unlike rapamycin, target both mTORC1 and mTORC2. Thus, we hypothesized that the complete inhibition of the PI3K/AKT/mTOR/HIF-1α axis with mTOR catalytic inhibitors and low doses of irinotecan may have antitumor effects. We showed that the AZD8055 and AZD2014 inhibitors were much more potent than rapamycin to reduce cell viability of four colon cell lines. On the other hand, whereas AZD2014 alone inhibits migration by 40%, the drug combination led to 70% inhibition. Similarly, neither irinotecan nor AZD2014 significantly reduced cell invasion, whereas a combination of the two inhibits invasion by 70%. In vivo, irinotecan and AZD2014 combination drastically reduced ectopic patient-derived colon tumor growth and this combination was more potent than Folfox or Folfiri. Finally, the combination totally inhibited liver and lung metastases developed from orthotopic implantation of SW480 cells. Thus, the use of mTOR catalytic inhibitors, in association with other chemotherapeutic agents like irinotecan at low doses, is potentially a hope for colon cancer treatment. |
format | Online Article Text |
id | pubmed-6826690 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68266902019-11-18 Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells Reita, Damien Bour, Cyril Benbrika, Radhia Groh, Audrey Pencreach, Erwan Guérin, Eric Guenot, Dominique Cancers (Basel) Article Advanced colorectal cancer has a poor prognosis because of metastasis formation and resistance to combined therapies. Downstream of PI3K/Akt and Ras/MAPK pathways, the mTOR kinase plays a decisive role in treatment failure. We previously established that irinotecan has antiangiogenic properties and it is known that new mammalian target of rapamycin (mTOR) catalytic AZD inhibitors, unlike rapamycin, target both mTORC1 and mTORC2. Thus, we hypothesized that the complete inhibition of the PI3K/AKT/mTOR/HIF-1α axis with mTOR catalytic inhibitors and low doses of irinotecan may have antitumor effects. We showed that the AZD8055 and AZD2014 inhibitors were much more potent than rapamycin to reduce cell viability of four colon cell lines. On the other hand, whereas AZD2014 alone inhibits migration by 40%, the drug combination led to 70% inhibition. Similarly, neither irinotecan nor AZD2014 significantly reduced cell invasion, whereas a combination of the two inhibits invasion by 70%. In vivo, irinotecan and AZD2014 combination drastically reduced ectopic patient-derived colon tumor growth and this combination was more potent than Folfox or Folfiri. Finally, the combination totally inhibited liver and lung metastases developed from orthotopic implantation of SW480 cells. Thus, the use of mTOR catalytic inhibitors, in association with other chemotherapeutic agents like irinotecan at low doses, is potentially a hope for colon cancer treatment. MDPI 2019-10-17 /pmc/articles/PMC6826690/ /pubmed/31627299 http://dx.doi.org/10.3390/cancers11101581 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Reita, Damien Bour, Cyril Benbrika, Radhia Groh, Audrey Pencreach, Erwan Guérin, Eric Guenot, Dominique Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells |
title | Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells |
title_full | Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells |
title_fullStr | Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells |
title_full_unstemmed | Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells |
title_short | Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells |
title_sort | synergistic anti-tumor effect of mtor inhibitors with irinotecan on colon cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826690/ https://www.ncbi.nlm.nih.gov/pubmed/31627299 http://dx.doi.org/10.3390/cancers11101581 |
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