title: Effect of pantoprazole to enhance activity of docetaxel against human tumour xenografts by inhibiting autophagy.
abstract: BACKGROUND
  Autophagy allows recycling of cellular components and may facilitate cell survival after chemotherapy. Pantoprazole inhibits proton pumps and is reported to inhibit autophagy. Here we evaluate the effects of pantoprazole to modify cytotoxicity of the anticancer drug docetaxel, and underlying mechanisms.
  
  
  METHODS
  Effects of docetaxel±pantoprazole were studied against wild-type and autophagy-deficient PC3 cells and against four human xenografts. Effects of pantoprazole on autophagy were evaluated by quantifying LC3-I, LC3-II and p62 proteins in western blots, and by fluorescent microscopy of cells transfected with RFP-GFP-LC3. The distribution of drug effects and of autophagy was quantified in tumour sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3, Ki67 and LC3/ p62.
  
  
  RESULTS
  Pantoprazole increased the toxicity of docetaxel in vitro, increased docetaxel-induced expression of γH2AX and cleaved caspase-3, and decreased Ki67 in tumour sections. Pantoprazole increased growth delay of four human xenografts of low, moderate and high sensitivity to docetaxel, with minimal increase in toxicity. Docetaxel led to increased autophagy throughout tumour sections. Pantoprazole inhibited autophagy, and effects of pantoprazole were reduced against genetically modified cells with decreased ability to undergo autophagy.
  
  
  CONCLUSIONS
  Autophagy is a mechanism of resistance to docetaxel chemotherapy that may be modified by pantoprazole to improve therapeutic index.
authors: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: Q
authors: Q
authors: Tan
authors: 1] Division of Medical Oncology and Hematology, Princess Margaret Cancer Center and University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9 [2] Institute of Medical Science, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: A M
authors: AM
authors: Joshua
authors: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: J K
authors: JK
authors: Saggar
authors: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: M
authors: M
authors: Yu
authors: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: M
authors: M
authors: Wang
authors: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: N
authors: N
authors: Kanga
authors: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: J Y
authors: JY
authors: Zhang
authors: Division of Medical Oncology and Hematology, Princess Margaret Cancer Center and University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: X
authors: X
authors: Chen
authors: Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: B G
authors: BG
authors: Wouters
authors: 1] Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9 [2] Division of Medical Oncology and Hematology, Princess Margaret Cancer Center and University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9 [3] Institute of Medical Science, University Health Network, University of Toronto, Toronto, ON, Canada M5G2M9.
authors: I F
authors: IF
authors: Tannock
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077402:Pantoprazole; D059010:Single-Cell Analysis; D043823:Taxoids / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D043823:Taxoids; D000077143:Docetaxel; D000077402:Pantoprazole
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