Teklab Gebregiworgis1, Fatema Bhinderwala1,2, Vinee Purohit3, Nina V Chaika3, Pankaj K Singh3,4,5,6, Robert Powers7,8. 1. Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA. 2. Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA. 3. The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA. 4. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA. 5. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA. 6. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA. 7. Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA. rpowers3@unl.edu. 8. Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA. rpowers3@unl.edu.
Abstract
INTRODUCTION: Gemcitabine is an important component of pancreatic cancer clinical management. Unfortunately, acquired gemcitabine resistance is widespread and there are limitations to predicting and monitoring therapeutic outcomes. OBJECTIVE: To investigate the potential of metabolomics to differentiate pancreatic cancer cells that develops resistance or respond to gemcitabine treatment. RESULTS: We applied 1D 1H and 2D 1H-13C HSQC NMR methods to profile the metabolic signature of pancreatic cancer cells. 13C6-glucose labeling identified 30 key metabolites uniquely altered between wild-type and gemcitabine-resistant cells upon gemcitabine treatment. Gemcitabine resistance was observed to reprogram glucose metabolism and to enhance the pyrimidine synthesis pathway. Myo-inositol, taurine, glycerophosphocholine and creatinine phosphate exhibited a "binary switch" in response to gemcitabine treatment and acquired resistance. CONCLUSION: Metabolic differences between naïve and resistant pancreatic cancer cells and, accordingly, their unique responses to gemcitabine treatment were revealed, which may be useful in the clinical setting for monitoring a patient's therapeutic response.
INTRODUCTION:Gemcitabine is an important component of pancreatic cancer clinical management. Unfortunately, acquired gemcitabine resistance is widespread and there are limitations to predicting and monitoring therapeutic outcomes. OBJECTIVE: To investigate the potential of metabolomics to differentiate pancreatic cancer cells that develops resistance or respond to gemcitabine treatment. RESULTS: We applied 1D 1H and 2D 1H-13C HSQC NMR methods to profile the metabolic signature of pancreatic cancer cells. 13C6-glucose labeling identified 30 key metabolites uniquely altered between wild-type and gemcitabine-resistant cells upon gemcitabine treatment. Gemcitabine resistance was observed to reprogram glucose metabolism and to enhance the pyrimidine synthesis pathway. Myo-inositol, taurine, glycerophosphocholine and creatinine phosphate exhibited a "binary switch" in response to gemcitabine treatment and acquired resistance. CONCLUSION: Metabolic differences between naïve and resistant pancreatic cancer cells and, accordingly, their unique responses to gemcitabine treatment were revealed, which may be useful in the clinical setting for monitoring a patient's therapeutic response.
Entities:
Keywords:
Drug resistance; Gemcitabine; NMR metabolomics; Pancreatic cancer
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