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Volume 11
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Article

Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer

by
Goran Hamid Mohammad
1,2,†,
Vessela Vassileva
3,†,
Pilar Acedo
1,
Steven W. M. Olde Damink
4,
Massimo Malago
5,
Dipok Kumar Dhar
1,6,‡ and
Stephen P. Pereira
1,*,‡
1
Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London NW3 2QG, UK
2
Komar Research Center, Komar University of Science and Technology, Sulaimani 46001, Iraq
3
Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0UQ, UK
4
Department of Surgery, Maastricht University Medical Center & Nutrim School for Nutrition, Toxicology and Metabolism, Maastricht University, 6200 MD Maastricht, The Netherlands
5
Hepato-pancreatic-biliary and Liver Transplantation Surgery, Royal Free Hospital Campus, University College London, London NW3 2QG, UK
6
King Faisal Specialist Hospital and Research Center, Comparative Medicine Department and Organ Transplantation Center, Riyadh 11211, Saudi Arabia
*
Author to whom correspondence should be addressed.
†
Joint first authors.
‡
Joint senior authors.
Cancers 2019, 11(9), 1372; https://doi.org/10.3390/cancers11091372
Submission received: 11 August 2019 / Revised: 7 September 2019 / Accepted: 12 September 2019 / Published: 16 September 2019
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Abstract

Reprogrammed glucose metabolism is one of the hallmarks of cancer, and increased expression of key glycolytic enzymes, such as pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), has been associated with poor prognosis in various malignancies. Targeting these enzymes could attenuate aerobic glycolysis and inhibit tumor proliferation. We investigated whether the PKM2 activator, TEPP-46, and the LDHA inhibitor, FX-11, can be combined to inhibit in vitro and in vivo tumor growth in preclinical models of pancreatic cancer. We assessed PKM2 and LDHA expression, enzyme activity, and cell proliferation rate after treatment with TEPP-46, FX-11, or a combination of both. Efficacy was validated in vivo by evaluating tumor growth, PK and LDHA activity in plasma and tumors, and PKM2, LDHA, and Ki-67 expression in tumor tissues following treatment. Dual therapy synergistically inhibited pancreatic cancer cell proliferation and significantly delayed tumor growth in vivo without apparent toxicity. Treatment with TEPP-46 and FX-11 resulted in increased PK and reduced LDHA enzyme activity in plasma and tumor tissues and decreased PKM2 and LDHA expression in tumors, which was reflected by a decrease in tumor volume and proliferation. The targeting of glycolytic enzymes such as PKM2 and LDHA represents a promising therapeutic approach for the treatment of pancreatic cancer.
Keywords: pancreatic cancer; pyruvate kinase M2; lactate dehydrogenase A; glycolytic enzymes; combination therapy pancreatic cancer; pyruvate kinase M2; lactate dehydrogenase A; glycolytic enzymes; combination therapy
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MDPI and ACS Style

Mohammad, G.H.; Vassileva, V.; Acedo, P.; Olde Damink, S.W.M.; Malago, M.; Dhar, D.K.; Pereira, S.P. Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer. Cancers 2019, 11, 1372. https://doi.org/10.3390/cancers11091372

AMA Style

Mohammad GH, Vassileva V, Acedo P, Olde Damink SWM, Malago M, Dhar DK, Pereira SP. Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer. Cancers. 2019; 11(9):1372. https://doi.org/10.3390/cancers11091372

Chicago/Turabian Style

Mohammad, Goran Hamid, Vessela Vassileva, Pilar Acedo, Steven W. M. Olde Damink, Massimo Malago, Dipok Kumar Dhar, and Stephen P. Pereira. 2019. "Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer" Cancers 11, no. 9: 1372. https://doi.org/10.3390/cancers11091372

APA Style

Mohammad, G. H., Vassileva, V., Acedo, P., Olde Damink, S. W. M., Malago, M., Dhar, D. K., & Pereira, S. P. (2019). Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer. Cancers, 11(9), 1372. https://doi.org/10.3390/cancers11091372

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