PMID- 31627299 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 11 IP - 10 DP - 2019 Oct 17 TI - Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells. LID - 10.3390/cancers11101581 [doi] LID - 1581 AB - 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-1alpha 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. FAU - Reita, Damien AU - Reita D AUID- ORCID: 0000-0001-6281-9909 AD - Progression Tumorale et Microenvironnement, Approches Translationnelles et Epidemiologie, EA3430, Universite de Strasbourg, F-67200 Strasbourg, France. damien.reita@gmail.com. AD - Laboratoire de Biochimie et Biologie Moleculaire, Hopitaux Universitaires de Strasbourg, 67200 Strasbourg, France. damien.reita@gmail.com. AD - Laboratory of Bioimagery and Pathologies, UMR7021 CNRS, University of Strasbourg, 67200 Strasbourg, France. damien.reita@gmail.com. AD - Federation de Medecine Translationnelle, 67000 Strasbourg, France. damien.reita@gmail.com. FAU - Bour, Cyril AU - Bour C AD - Progression Tumorale et Microenvironnement, Approches Translationnelles et Epidemiologie, EA3430, Universite de Strasbourg, F-67200 Strasbourg, France. cyril.bour@unistra.fr. AD - Federation de Medecine Translationnelle, 67000 Strasbourg, France. cyril.bour@unistra.fr. AD - U1113 INSERM/Unistra, IRFAC - Interface de Recherche Fondamentale et Appliquee en Cancerologie, F-67200 Strasbourg, France. cyril.bour@unistra.fr. FAU - Benbrika, Radhia AU - Benbrika R AD - Progression Tumorale et Microenvironnement, Approches Translationnelles et Epidemiologie, EA3430, Universite de Strasbourg, F-67200 Strasbourg, France. radhiabenbrika@gmail.com. AD - Federation de Medecine Translationnelle, 67000 Strasbourg, France. radhiabenbrika@gmail.com. FAU - Groh, Audrey AU - Groh A AUID- ORCID: 0000-0002-7881-9089 AD - Progression Tumorale et Microenvironnement, Approches Translationnelles et Epidemiologie, EA3430, Universite de Strasbourg, F-67200 Strasbourg, France. groh.audrey@orange.fr. AD - Federation de Medecine Translationnelle, 67000 Strasbourg, France. groh.audrey@orange.fr. FAU - Pencreach, Erwan AU - Pencreach E AD - Progression Tumorale et Microenvironnement, Approches Translationnelles et Epidemiologie, EA3430, Universite de Strasbourg, F-67200 Strasbourg, France. erwan.pencreach@chru-strasbourg.fr. AD - Laboratoire de Biochimie et Biologie Moleculaire, Hopitaux Universitaires de Strasbourg, 67200 Strasbourg, France. erwan.pencreach@chru-strasbourg.fr. AD - Federation de Medecine Translationnelle, 67000 Strasbourg, France. erwan.pencreach@chru-strasbourg.fr. AD - U1113 INSERM/Unistra, IRFAC - Interface de Recherche Fondamentale et Appliquee en Cancerologie, F-67200 Strasbourg, France. erwan.pencreach@chru-strasbourg.fr. FAU - Guerin, Eric AU - Guerin E AUID- ORCID: 0000-0003-1388-2834 AD - Progression Tumorale et Microenvironnement, Approches Translationnelles et Epidemiologie, EA3430, Universite de Strasbourg, F-67200 Strasbourg, France. Eric.GUERIN@chru-strasbourg.fr. AD - Laboratoire de Biochimie et Biologie Moleculaire, Hopitaux Universitaires de Strasbourg, 67200 Strasbourg, France. Eric.GUERIN@chru-strasbourg.fr. AD - Federation de Medecine Translationnelle, 67000 Strasbourg, France. Eric.GUERIN@chru-strasbourg.fr. AD - U1113 INSERM/Unistra, IRFAC - Interface de Recherche Fondamentale et Appliquee en Cancerologie, F-67200 Strasbourg, France. Eric.GUERIN@chru-strasbourg.fr. FAU - Guenot, Dominique AU - Guenot D AD - Progression Tumorale et Microenvironnement, Approches Translationnelles et Epidemiologie, EA3430, Universite de Strasbourg, F-67200 Strasbourg, France. guenot@unistra.fr. AD - Federation de Medecine Translationnelle, 67000 Strasbourg, France. guenot@unistra.fr. AD - U1113 INSERM/Unistra, IRFAC - Interface de Recherche Fondamentale et Appliquee en Cancerologie, F-67200 Strasbourg, France. guenot@unistra.fr. LA - eng GR - XXX/Universite de Strasbourg/ GR - XXX/Societe nationale de gastro-enterologie/ GR - XXX/Fondation de France/ GR - XXX/HUS strasbourg/ PT - Journal Article DEP - 20191017 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC6826690 OTO - NOTNLM OT - AZD2014 OT - Irinotecan OT - colon cancer OT - mTOR OT - metastasis OT - orthotopic xenograft COIS- The authors declare no conflict of interest. EDAT- 2019/10/20 06:00 MHDA- 2019/10/20 06:01 PMCR- 2019/10/17 CRDT- 2019/10/20 06:00 PHST- 2019/07/04 00:00 [received] PHST- 2019/10/02 00:00 [revised] PHST- 2019/10/11 00:00 [accepted] PHST- 2019/10/20 06:00 [entrez] PHST- 2019/10/20 06:00 [pubmed] PHST- 2019/10/20 06:01 [medline] PHST- 2019/10/17 00:00 [pmc-release] AID - cancers11101581 [pii] AID - cancers-11-01581 [pii] AID - 10.3390/cancers11101581 [doi] PST - epublish SO - Cancers (Basel). 2019 Oct 17;11(10):1581. doi: 10.3390/cancers11101581.