Lactate dehydrogenase A inhibition by small molecular entities: steps in the right direction.

Btissame El Hassouni,Christian M Vonk,Filippo Minutolo,Valentina M Gomez,Mjriam Capula,Elisa Giovannetti,Marika Franczak,Ryszard T Smolenski,Carlotta Granchi,Godefridus J Peters

doi:10.18632/oncoscience.519

Abstract

Direct targeting of energy metabolism to defeat cancer is not a recent strategy. Although quite a few drugs use cellular metabolism for their antitumor effect, no direct inhibitors of energy metabolism have been approved by the FDA. Currently, several inhibitors of lactate dehydrogenase A (LDH-A), a key player in glycolysis, are in development. Earlier, we demonstrated the efficacy of N-hydroxyindole-based LDH-A inhibitors in different cancer types. In this study we describe the efficacy of NHI-Glc-2, which is designed to dual target cancer cells, by exploiting a simultaneous enhanced glucose uptake by overexpressed glucose transporter 1 (GLUT1) and by inhibition of LDH-A. NHI-Glc-2 inhibits LDH-A enzyme activity, PANC-1 cell growth and disrupts spheroid integrity, with an overall effect that is more pronounced when combined with gemcitabine.

Highlights

The high proliferation rate of cancer cells requires sufficient supply of nutrients to enable cell growth [1]
We reported an increased sensitivity to N-hydroxyindole-based lactate dehydrogenase A (LDH-A) inhibitors, NHI-I and NHI-2, in pancreatic cancer cells growing under hypoxic conditions [8]
LDH-A is overexpressed in various types of cancer [11,12,13], and contributes to the aberrant metabolism that stimulates cancer growth and invasion

Summary

Introduction

The high proliferation rate of cancer cells requires sufficient supply of nutrients to enable cell growth [1]. One of the pathways that is upregulated to provide this increased nutrient demand, is glucose metabolism, i.e. glycolysis. The last essential step in this pathway is lactate dehydrogenase A (LDH-A), which catalyzes the conversion of pyruvate to lactate using nicotinamide adenine dinucleotide (NADH) as a cofactor. The overexpression of LDH-A contributes to an increased production of lactate, which causes a decrease in the pH of the tumour microenvironment. Both acidification and extracellular accumulation of lactate, contribute to the suppression of immune effectors [4], cause antioxidant defenses against chemotherapeutics [5] and favour tumour invasion [6]

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Results

Conclusion