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.
Highlights
Cancer cells consume nutrients differently than normal cells, with increased glycolysis present in almost all primary and metastatic cancers [1, 2]
While administration of the pyruvate kinase isozyme M2 (PKM2) activator, DASA-58, on H1299 cells did not result in increased glucose uptake [11], we observed higher glucose consumption from cell culture media when the same cells were treated with another activator, TEPP-46 that was significantly different from vehicle treatment after 48 hr (1.6 ± 0.6 mM vs. 3.6 ± 0.4 mM, p < 0.05) (Figure 1A)
While TEPP-46 reduced viability of tumor-initiating cells (TICs)’s, we investigated the ability of other metabolic inhibitors that could synergize with PKM2 activation to cause reduced viability in established cancer cell lines
Summary
Cancer cells consume nutrients differently than normal cells, with increased glycolysis present in almost all primary and metastatic cancers [1, 2]. Alternate splicing of the PKM gene results in differential expression of PK isoforms, with PKM2 expressed in cells with high rates of nucleic acid synthesis, including most cancer cells [5,6,7]. PKM2 has emerged as a new target for cancer therapeutics using both smallmolecule inhibitors [9, 10] and activators of the enzyme that enhance tetramerization of PKM2 subunits thereby increasing enzyme activity [11, 12]. Considering the seemingly contradictory data available on PKM2 as a drug target as well www.impactjournals.com/oncotarget as the modest effect of small molecules targeting this enzyme alone, the investigation of additional drugs that synergize PKM2 activation is much needed
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