title: Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation.
abstract: BACKGROUND
  Targeting both mitochondrial bioenergetics and glycolysis pathway is an effective way to inhibit proliferation of tumour cells, including those that are resistant to conventional chemotherapeutics.
  
  
  METHODS
  In this study, using the Seahorse 96-well Extracellular Flux Analyzer, we mapped the two intrinsic cellular bioenergetic parameters, oxygen consumption rate and proton production rate in six different pancreatic cancer cell lines and determined their differential sensitivity to mitochondrial and glycolytic inhibitors.
  
  
  RESULTS
  There exists a very close relationship among intracellular bioenergetic parameters, depletion of ATP and anti-proliferative effects (inhibition of colony-forming ability) in pancreatic cancer cells derived from different genetic backgrounds treated with the glycolytic inhibitor, 2-deoxyglucose (2-DG). The most glycolytic pancreatic cancer cell line was exquisitely sensitive to 2-DG, whereas the least glycolytic pancreatic cancer cell was resistant to 2-DG. However, when combined with metformin, inhibitor of mitochondrial respiration and activator of AMP-activated protein kinase, 2-DG synergistically enhanced ATP depletion and inhibited cell proliferation even in poorly glycolytic, 2-DG-resistant pancreatic cancer cell line. Furthermore, treatment with conventional chemotherapeutic drugs (e.g., gemcitabine and doxorubicin) or COX-2 inhibitor, celecoxib, sensitised the cells to 2-DG treatment.
  
  
  CONCLUSIONS
  Detailed profiling of cellular bioenergetics can provide new insight into the design of therapeutic strategies for inhibiting pancreatic cancer cell metabolism and proliferation.
authors.affiliation: Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: G
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zielonka
authors.affiliation: 1] Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA [2] Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: D
authors.initials: D
authors.lastname: McAllister
authors.affiliation: Department of Surgery/Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tsai
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Dwinell
authors.affiliation: Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kalyanaraman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000068579:Celecoxib; D018929:Cell Culture Techniques; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D006859:Hydrogen / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D013449:Sulfonamides; D003841:Deoxycytidine; D006859:Hydrogen; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D008687:Metformin; D003847:Deoxyglucose; D000068579:Celecoxib; D000093542:Gemcitabine