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Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue
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Lactate dehydrogenase A inhibition by small molecular entities: steps in the right direction

Btissame El Hassouni1, Marika Franczak2, Mjriam Capula3

  • 1Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, Amsterdam, Netherlands.

Oncoscience
|November 16, 2020
PubMed

Insights

This study introduces NHI-Glc-2, a novel dual-targeting agent that inhibits lactate dehydrogenase A (LDH-A) and exploits enhanced glucose uptake in cancer cells. NHI-Glc-2 shows promise in reducing cancer cell growth and spheroid integrity, especially when combined with gemcitabine.

Area of Science:

  • Biochemistry
  • Oncology
  • Pharmacology

Background:

  • Targeting cancer cell metabolism is a known antitumor strategy.
  • Lactate dehydrogenase A (LDH-A), crucial in glycolysis, is a key target for cancer therapy.
  • No direct inhibitors of energy metabolism have received FDA approval yet.

Purpose of the Study:

  • To evaluate the efficacy of NHI-Glc-2, a novel dual-targeting agent designed to inhibit LDH-A and exploit enhanced glucose uptake via glucose transporter 1 (GLUT1).
  • To assess the impact of NHI-Glc-2 on PANC-1 cancer cell growth and spheroid integrity.
  • To investigate the combined effect of NHI-Glc-2 and gemcitabine on cancer cells.

Main Methods:

  • Design and synthesis of NHI-Glc-2, a dual-targeting inhibitor.
  • Enzyme inhibition assays for LDH-A activity.
  • Cell viability assays using PANC-1 cancer cells.
  • Spheroid integrity disruption assays.
  • Combination studies with gemcitabine.

Main Results:

  • NHI-Glc-2 effectively inhibits LDH-A enzyme activity.
  • The compound reduces PANC-1 cell growth and disrupts cancer cell spheroid integrity.
  • The combined treatment of NHI-Glc-2 and gemcitabine demonstrated a more pronounced antitumor effect.

Conclusions:

  • NHI-Glc-2 represents a promising dual-targeting strategy for cancer therapy by inhibiting LDH-A and leveraging enhanced glucose uptake.
  • The compound exhibits significant efficacy in inhibiting cancer cell proliferation and disrupting tumor structure.
  • Combination therapy with gemcitabine may enhance the therapeutic potential of NHI-Glc-2 for cancer treatment.
Keywords:
LDH-ANHI-Glc-2glycolysiswarburg

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