title: Up-regulation of autophagy is a mechanism of resistance to chemotherapy and can be inhibited by pantoprazole to increase drug sensitivity.
abstract: BACKGROUND
  Autophagy is a survival mechanism that allows recycling of cellular breakdown products, particularly in stressed cells. Here we evaluate the hypotheses that up-regulation of autophagy is a common mechanism of resistance to chemotherapy, and that drug resistance can be reversed by inhibiting autophagy with a proton pump inhibitor.
  
  
  METHODS
  We exposed human PC3, LNCaP and MCF7 cells to seven clinically-used chemotherapy drugs ± pantoprazole, examined the up-regulation of autophagy and the effect on cellular proliferation by Western Blots, MTS assay and colony-forming assay. The distribution of drug effects and of autophagy was quantified in LNCaP tumor sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3 and p62.
  
  
  RESULTS
  All anticancer drugs led to up-regulation of autophagy in cultured tumor cells. Pantoprazole inhibited the induction of autophagy in a time- and dose-dependent manner, and sensitized cancer cells to the seven anti-cancer drugs. Treatment of LNCaP xenografts with paclitaxel induced both DNA damage and autophagy; autophagy was inhibited and markers of toxicity were increased by pantoprazole.
  
  
  CONCLUSIONS
  Induction of autophagy is a general mechanism associated with resistance to anticancer drugs and that its inhibition is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes.
authors.affiliation: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada. susie.tan@uhnres.utoronto.ca.|Princess Margaret Cancer Center, 9 floor room 417, 610 University Ave, Toronto, ON, M5G2M9, Canada. susie.tan@uhnres.utoronto.ca.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tan
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University Health Network, University of Toronto, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Joshua
authors.affiliation: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada.|Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: R G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: B G
authors.initials: BG
authors.lastname: Wouters
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: Allen
authors.affiliation: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada. ian.tannock@uhn.ca.|Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University Health Network, University of Toronto, Toronto, ON, Canada. ian.tannock@uhn.ca.|Princess Margaret Cancer Center, 9 floor room 417, 610 University Ave, Toronto, ON, M5G2M9, Canada. ian.tannock@uhn.ca.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D001808:Blood Vessels / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D054328:Proton Pump Inhibitors; D000077402:Pantoprazole; D017239:Paclitaxel
keywords: Autophagy; Drug distribution; Pharmacodynamic markers; Proton pump inhibitor; Tumor microenvironment