title: Tumour hypoxia determines the potential of combining mTOR and autophagy inhibitors to treat mammary tumours.
abstract: BACKGROUND
  Hypoxia can activate autophagy, a self-digest adaptive process that maintains cell turnover. Mammalian target of rapamycin (mTOR) inhibitors are used to treat cancer but also stimulate autophagy.
  
  
  METHODS
  Human mammary cancer cells and derived xenografts were used to examine whether hypoxia could exacerbate autophagy-mediated resistance to the mTOR inhibitor rapamycin.
  
  
  RESULTS
  Rapamycin exerted potent antitumour effects in MCF-7 and MDA-MB-231 mammary tumours through a marked inhibition of angiogenesis, but the autophagy inhibitor chloroquine (CQ) failed to further sensitise tumours to mTOR inhibition. Rapamycin treatment actually led to tumour reoxygenation, thereby preventing the development of autophagy. Chloroquine alone, however, blocked the growth of MCF-7 tumours and in vitro blunted the hypoxia-induced component of autophagy in these cells. Finally, when initiating CQ treatment in large, hypoxic tumours, a robust antitumour effect could be observed, which also further increased the antiproliferative effects of rapamycin.
  
  
  CONCLUSIONS
  The mTOR inhibitor rapamycin significantly contributes to tumour growth inhibition and normalisation of the tumour vasculature through potent antiangiogenic effects. The resulting reduction in hypoxia accounts for a lack of sensitisation by the autophagy inhibitor CQ, except if the tumours are already at an advanced stage, and thus largely hypoxic at the initiation of the combination of rapamycin and CQ treatment.
authors.affiliation: 1] Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), 53 Avenue East Mounier, B1.53.09, Brussels 1200, Belgium [2] Pole of Molecular Imaging, Radiotherapy and Oncology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Luc, Brussels, Belgium [3] Department of Medical Oncology, Centre du Cancer, Cliniques universitaires Saint-Luc, Brussels, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Seront
authors.forename: R
authors.initials: R
authors.lastname: Boidot
authors.forename: C
authors.initials: C
authors.lastname: Bouzin
authors.forename: O
authors.initials: O
authors.lastname: Karroum
authors.forename: B F
authors.initials: BF
authors.lastname: Jordan
authors.forename: B
authors.initials: B
authors.lastname: Gallez
authors.forename: J-P
authors.initials: JP
authors.lastname: Machiels
authors.forename: O
authors.initials: O
authors.lastname: Feron
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002738:Chloroquine / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002738:Chloroquine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus