title: Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy.
abstract: OBJECTIVE
  Autophagy is a critical survival pathway for cancer cells under conditions of nutrient or oxygen limitation, or cell stress. As a consequence of antiangiogenic therapy, solid tumors encounter hypoxia induction and imbalances in nutrient supply. We wished to determine the role of autophagy in protection of tumor cells from the effects of antiangiogenic therapy and chemotherapy. We examined the effect of inhibiting autophagy on hypoxic colon cancer cells in vitro and on bevacizumab- and oxaliplatin-treated mouse xenografts in vivo.
  
  
  METHODS
  The autophagic response to hypoxia and DNA-damaging agents was assessed by fluorescent microscopic imaging, autophagy-related gene expression, and by electron microscopic ultrastructural analysis. Pharmacologic and molecular approaches to autophagy inhibition were taken in a panel of colon cancer cell lines. Mouse xenograft models were treated with combinations of oxaliplatin, bevacizumab, and chloroquine to assess effects on tumor growth reduction and on pharmacodynamic markers of autophagy inhibition.
  
  
  RESULTS
  Autophagy was induced in colon cancer models by exposure to both hypoxia and oxaliplatin. Inhibition of autophagy, either with chloroquine or by downregulation of beclin1 or of ATG5, enhanced sensitivity to oxaliplatin under normal and hypoxic conditions in a synergistic manner. Both bevacizumab and oxaliplatin treatments activate autophagy in HT29 murine xenografts. The addition of chloroquine to bevacizumab-based treatment provided greater tumor control in concert with evidence of autophagy inhibition.
  
  
  CONCLUSIONS
  These findings implicate autophagy as a mechanism of resistance to antiangiogenic therapies and support investigation of inhibitory approaches in the management of this disease.
authors: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA.
authors: Muthu
authors: M
authors: Selvakumaran
authors: Ravi K
authors: RK
authors: Amaravadi
authors: Irina A
authors: IA
authors: Vasilevskaya
authors: Peter J
authors: PJ
authors: O'Dwyer
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D000068258:Bevacizumab; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D002738:Chloroquine