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

Sui Seng Tee1,2, Jae Mo Park1,3,4, Ralph E Hurd5

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

Oncotarget
|December 7, 2017
PubMed

Insights

Combining a pyruvate kinase isozyme M2 (PKM2) activator with 2-deoxy-D-glucose (2-DG) reduces established tumor growth. This combination therapy shows promise for cancer treatment, with non-invasive imaging to monitor effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cancer metabolism is a key target for anti-tumor therapies.
  • Pyruvate kinase isozyme M2 (PKM2) activators inhibit tumor formation.
  • The effect of PKM2 activators on established tumors is not well understood.

Purpose of the Study:

  • To investigate the efficacy of a PKM2 activator, TEPP-46, on established tumors.
  • To explore the combination of PKM2 activators with 2-deoxy-D-glucose (2-DG).
  • To assess the metabolic changes induced by the combination therapy using hyperpolarized magnetic resonance spectroscopy (MRS).

Main Methods:

  • Treatment of cancer cell lines and established subcutaneous tumors with TEPP-46 and/or 2-DG.
  • Assessment of cell viability and tumor growth.
  • Utilizing hyperpolarized 13C-MRS to monitor metabolic flux in vivo.

Main Results:

  • TEPP-46 treatment increased glucose consumption in cancer cells.
  • Combination treatment of TEPP-46 and 2-DG significantly reduced cancer cell viability and established tumor growth.
  • Hyperpolarized 13C-MRS detected increased pyruvate to lactate exchange in combination-treated tumors, indicating enhanced metabolic perturbation.

Conclusions:

  • PKM2 activators combined with 2-DG represent a promising therapeutic strategy for established tumors.
  • Combination therapy demonstrates synergistic anti-tumor effects.
  • Non-invasive metabolic imaging using MRS can accelerate the clinical translation of novel cancer metabolism-targeting drugs.
Keywords:
PKM2cancer metabolismhyperpolarized MRImetabolic imagingmolecular imaging

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