PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose
PDF | HTML | Supplementary Files | How to cite
Metrics: PDF 1534 views | HTML 3091 views | ?
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
Sui Seng Tee, email: [email protected]
Keywords: molecular imaging, metabolic imaging, hyperpolarized MRI, cancer metabolism, PKM2
Received: October 19, 2016 Accepted: July 06, 2017 Published: July 26, 2017
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.