, 14:156 | Cite as

Insights into gemcitabine resistance and the potential for therapeutic monitoring

  • Teklab Gebregiworgis
  • Fatema Bhinderwala
  • Vinee Purohit
  • Nina V. Chaika
  • Pankaj K. Singh
  • Robert Powers
Short Communication



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.


To investigate the potential of metabolomics to differentiate pancreatic cancer cells that develops resistance or respond to gemcitabine treatment.


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.


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.


NMR metabolomics Pancreatic cancer Gemcitabine Drug resistance 



This work was supported in part by funding from the National Institutes of Health Grant No. (R01 CA163649, NCI) to P.K.S. and R.P.; the Redox Biology Center (Grant No. P30 GM103335, NIGMS) to R.P.; the Nebraska Center for Integrated Biomolecular Communication (Grant No. P20 GM113126, NIGMS) to R.P.; American Association for Cancer Research (AACR)-Pancreatic Cancer Action Network (PanCAN) Career Development Award (Grant No. 30-20-25-SING) to P.K.S.; the Specialized Programs for Research Excellence (Grant No. SPORE, 2P50 CA127297, NCI) to P.K.S.; Pancreatic Tumor Microenvironment Research Network (Grant No. U54, CA163120, NCI) to P.K.S.; and Fred & Pamela Buffett Cancer Center Support Grant (Grant No. P30CA036727) to P.K.S. and R.P. The research was performed in facilities renovated with support from the National Institutes of Health (Grant No. RR015468-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

11306_2018_1452_MOESM1_ESM.pdf (586 kb)
Supplementary material 1 (PDF 585 KB)


  1. Amelio, I., Cutruzzola, F., Antonov, A., Agostini, M., & Melino, G. (2014). Serine and glycine metabolism in cancer. Trends in Biochemical Sciences, 39(4), 191–198. Scholar
  2. Bardin, C., Veal, G., Paci, A., Chatelut, E., Astier, A., Leveque, D., et al. (2014). Therapeutic drug monitoring in cancer–are we missing a trick? European Journal of Cancer, 50(12), 2005–2009. Scholar
  3. Chaika, N. V., Gebregiworgis, T., Lewallen, M. E., Purohit, V., Radhakrishnan, P., Liu, X., et al. (2012). MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 109(34), 13787–13792. Scholar
  4. Comerford, S. A., Huang, Z., Du, X., Wang, Y., Cai, L., Witkiewicz, A. K., et al. (2014). Acetate dependence of tumors. Cell, 159(7), 1591–1602. Scholar
  5. Davies, J., & Davies, D. (2010). Origins and evolution of antibiotic resistance. Microbiology and Molecular Biology Reviews, 74(3), 417–433. Scholar
  6. de S. Cavalcante, L., & Monteiro, G. (2014). Gemcitabine: Metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. European Journal of Pharmacology, 741, 8–16. Scholar
  7. Fryer, R. A., Barlett, B., Galustian, C., & Dalgleish, A. G. (2011). Mechanisms underlying gemcitabine resistance in pancreatic cancer and sensitisation by the iMiD lenalidomide. Anticancer Research, 31(11), 3747–3756.PubMedGoogle Scholar
  8. Gardner, S. G., Somerville, G. A., Marshall, D. D., Powers, R., Daum, R. S., Daum, R. S., et al. (2018). Metabolic mitigation of Staphylococcus aureus vancomycin intermediate-level susceptibility. Antimicrobial Agents and Chemotherapy. 62(1), e01608–e01617.Google Scholar
  9. Gaupp, R., Lei, S., Reed, J. M., Peisker, H., Boyle-Vavra, S., Bayer, A. S., et al. (2015). Staphylococcus aureus metabolic adaptations during the transition from a daptomycin susceptibility phenotype to a daptomycin nonsusceptibility phenotype. Antimicrobial Agents and Chemotherapy, 59(7), 4226–4238. Scholar
  10. Gazdar, A. F., Zweig, M. H., Carney, D. N., Van Steirteghen, A. C., Baylin, S. B., & Minna, J. D. (1981). Levels of creatine kinase and its BB isoenzyme in lung cancer specimens and cultures. Cancer Research, 41(7), 2773–2777.PubMedGoogle Scholar
  11. Gebregiworgis, T., & Powers, R. (2012). Application of NMR metabolomics to search for human disease biomarkers. Combinatorial Chemistry & High Throughput Screening, 15(8), 595–610.CrossRefGoogle Scholar
  12. Gebregiworgis, T., Purohit, V., Shukla, S. K., Tadros, S., Chaika, N. V., Abrego, J., et al. (2017). Glucose limitation alters glutamine metabolism in MUC1-overexpressing pancreatic cancer cells. Journal of Proteome Research, 16(10), 3536–3546. Scholar
  13. Glunde, K., Penet, M. F., Jiang, L., Jacobs, M. A., & Bhujwalla, Z. M. (2015). Choline metabolism-based molecular diagnosis of cancer: An update. Expert Review of Molecular Diagnostics, 15(6), 735–747. Scholar
  14. Hara, T., Kosaka, N., & Kishi, H. (1998). PET imaging of prostate cancer using carbon-11-choline. Journal of Nuclear Medicine, 39(6), 990–995.PubMedGoogle Scholar
  15. Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., et al. (2014). Drug resistance in cancer: An overview. Cancers (Basel), 6(3), 1769–1792. Scholar
  16. Ju, H. Q., Gocho, T., Aguilar, M., Wu, M., Zhuang, Z. N., Fu, J., et al. (2015). Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through the redox modulation. Molecular Cancer Therapeutics, 14(3), 788–798. Scholar
  17. Lu, S. C. (2009). Regulation of glutathione synthesis. Molecular Aspects of Medicine, 30(1–2), 42–59. Scholar
  18. Matsubara, J., Ono, M., Honda, K., Negishi, A., Ueno, H., Okusaka, T., et al. (2010). Survival prediction for pancreatic cancer patients receiving gemcitabine treatment. Molecular & Cellular Proteomics, 9(4), 695–704. Scholar
  19. Rahman, M., & Hasan, M. R. (2015). Cancer metabolism and drug resistance. Metabolites, 5(4), 571–600. Scholar
  20. Raykov, Z., Grekova, S. P., Bour, G., Lehn, J. M., Giese, N. A., Nicolau, C., et al. (2014). Myo-inositol trispyrophosphate-mediated hypoxia reversion controls pancreatic cancer in rodents and enhances gemcitabine efficacy. International Journal of Cancer, 134(11), 2572–2582. Scholar
  21. Shukla, S. K., Purohit, V., Mehla, K., Gunda, V., Chaika, N. V., Vernucci, E., et al. (2017). MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell, 32(1), 71–87. (e77)CrossRefPubMedPubMedCentralGoogle Scholar
  22. Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M. H., Zhang, L., et al. (2016). Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature, 536(7617), 479–483. Scholar
  23. Tu, S., Zhang, X., Luo, D., Liu, Z., Yang, X., Wan, H., et al. (2015). Effect of taurine on the proliferation and apoptosis of human hepatocellular carcinoma HepG2 cells. Experimental and Therapeutic Medicine, 10(1), 193–200. Scholar
  24. Uhr, K., Prager-van der Smissen, W. J., Heine, A. A., Ozturk, B., Smid, M., Gohlmann, H. W., et al. (2015). Understanding drugs in breast cancer through drug sensitivity screening. Springerplus, 4, 611. Scholar
  25. Vucenik, I., & Shamsuddin, A. M. (2003). Cancer inhibition by inositol hexaphosphate (IP6) and inositol: From laboratory to clinic. Journal of Nutrition, 133(11 Suppl 1), 3778S–3784S.CrossRefGoogle Scholar
  26. Worley, B., & Powers, R. (2014). MVAPACK: A complete data handling package for NMR metabolomics. ACS Chemical Biology, 9(5), 1138–1144. Scholar
  27. Yang, M., & Vousden, K. H. (2016). Serine and one-carbon metabolism in cancer. Nature Reviews Cancer, 16(10), 650–662. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of Nebraska-LincolnLincolnUSA
  2. 2.Nebraska Center for Integrated Biomolecular CommunicationUniversity of Nebraska-LincolnLincolnUSA
  3. 3.The Eppley Institute for Research in Cancer and Allied DiseasesUniversity of Nebraska Medical CenterOmahaUSA
  4. 4.Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaUSA
  5. 5.Department of Pathology and MicrobiologyUniversity of Nebraska Medical CenterOmahaUSA
  6. 6.Department of Genetics, Cell Biology and AnatomyUniversity of Nebraska Medical CenterOmahaUSA

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