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Open AccessArticle

Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells

by Damien Reita 1,2,3,4,*, Cyril Bour 1,4,5, Radhia Benbrika 1,4, Audrey Groh 1,4, Erwan Pencreach 1,2,4,5, Eric Guérin 1,2,4,5 and Dominique Guenot 1,4,5
1
Progression Tumorale et Microenvironnement, Approches Translationnelles et Epidémiologie, EA3430, Université de Strasbourg, F-67200 Strasbourg, France
2
Laboratoire de Biochimie et Biologie Moléculaire, Hôpitaux Universitaires de Strasbourg, 67200 Strasbourg, France
3
Laboratory of Bioimagery and Pathologies, UMR7021 CNRS, University of Strasbourg, 67200 Strasbourg, France
4
Fédération de Médecine Translationnelle, 67000 Strasbourg, France
5
U1113 INSERM/Unistra, IRFAC – Interface de Recherche Fondamentale et Appliquée en Cancérologie, F-67200 Strasbourg, France
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1581; https://doi.org/10.3390/cancers11101581
Received: 4 July 2019 / Revised: 2 October 2019 / Accepted: 11 October 2019 / Published: 17 October 2019
(This article belongs to the Collection Kinases and Cancer)
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. View Full-Text
Keywords: mTOR; Irinotecan; AZD2014; colon cancer; metastasis; orthotopic xenograft mTOR; Irinotecan; AZD2014; colon cancer; metastasis; orthotopic xenograft
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MDPI and ACS Style

Reita, D.; Bour, C.; Benbrika, R.; Groh, A.; Pencreach, E.; Guérin, E.; Guenot, D. Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells. Cancers 2019, 11, 1581.

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