Oncotarget

Research Papers:

PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose

Sui Seng Tee _, Jae Mo Park, Ralph E. Hurd, Kyle R. Brimacombe, Matthew B. Boxer, Tarik F. Massoud, Brian K. Rutt and Daniel M. Spielman

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Oncotarget. 2017; 8:90959-90968. https://doi.org/10.18632/oncotarget.19630

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Abstract

Sui Seng Tee1,5,*, Jae Mo Park1,6,7,*, Ralph E. Hurd2, Kyle R. Brimacombe3,4, Matthew B. Boxer3, Tarik F. Massoud1, Brian K. Rutt1 and Daniel M. Spielman1

1Department of Radiology, Stanford University, Stanford, CA, USA

2Applied Sciences Laboratory, GE Healthcare, Menlo Park, CA, USA

3National Center for Advancing Translational Sciences, NIH, Bethesda, MD, USA

4NIH Chemical Genomics Center, Bethesda, MD, USA

5Current/Present address: Memorial Sloan Kettering Cancer Center, New York, NY, USA

6Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

7Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

*These authors have contributed equally to this work

Correspondence to:

Sui Seng Tee, email: tees@mskcc.org

Keywords: molecular imaging, metabolic imaging, hyperpolarized MRI, cancer metabolism, PKM2

Received: October 19, 2016    Accepted: July 06, 2017    Published: July 26, 2017

ABSTRACT

Cancer metabolism has emerged as an increasingly attractive target for interfering with tumor growth. Small molecule activators of pyruvate kinase isozyme M2 (PKM2) suppress tumor formation but have an unknown effect on established tumors. We demonstrate that TEPP-46, a PKM2 activator, results in increased glucose consumption, providing the rationale for combining PKM2 activators with the toxic glucose analog, 2-deoxy-D-glucose (2-DG). Combination treatment resulted in reduced viability of a range of cell lines in standard cell culture conditions at concentrations of drugs that had no effect when used alone. This effect was replicated in vivo on established subcutaneous tumors. We further demonstrated the ability to detect acute metabolic differences in combination treatment using hyperpolarized magnetic resonance spectroscopy (MRS). Combination treated tumors displayed a higher pyruvate to lactate 13C-label exchange 2 hr post-treatment. This ability to assess the effect of drugs non-invasively may accelerate the implementation and clinical translation of drugs that target cancer metabolism.


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