Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression

Abstract

As the result of genetic alterations and tumor hypoxia, many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A (LDHA), which is encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1). Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation, but its role in tumor maintenance and progression has not been established. Furthermore, how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is not well understood. Here, we report that reduction of LDHA by siRNA or its inhibition by a small-molecule inhibitor (FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid]) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine. Furthermore, we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts. When used in combination with the NAD + synthesis inhibitor FK866, FX11 induced lymphoma regression. Hence, inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors. Our studies document a therapeutical approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutical targeting of cancer energy metabolism.glycolysis | lymphoma | pancreatic cancer | redox stress | xenograft models

Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma

“…LDHA may catalyse the conversion of pyruvate and NADH to lactate and NAD þ (ref. 47), thus facilitating the carbon flow for glycolysis, as NAD þ is necessary for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to catalyse glyceraldehyde 3-phosphate to 1, 3-bisphosphoglycerate 48 . On the other hand, GPDH reduces dihydroxyacetone phosphate into glycerol 3-phosphate and allows the prompt dephosphorylation of glycerol 3-phosphate into glycerol, thus having a major role in glyceroneogenesis 49 .…”

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

“…The MYC oncogene contributes to tumorigenesis of many types of cancer through various mechanisms (7)(8)(9)(10), including the regulation of proliferation and growth, protein and ribosomal biogenesis, changes in metabolism, lipid synthesis, and induction of angiogenesis (11)(12)(13)(14). MYC reprogramming can result in tumors that are addicted to glucose and/or glutamine for their energy metabolism (15)(16)(17)(18)(19). MYC directly regulates specific genes of the glycolytic and glutaminolytic pathways (15,17,20,21), including lactate dehydrogenase A (LDHA), glucose transporter 1 (Glut1), hexokinase 2 (HK2), phosphofructokinase-M 1 (PFKM1), and enolase 1 (Eno1) (21)(22)(23).…”

Inhibition of Glycolytic Enzymes Mediated by Pharmacologically Activated p53

“…Several glycolysis inhibitors are in preclinical and clinical development, such as lactate dehydrogenase A inhibitor FX11 (12) or hexokinase inhibitor 2-deoxyglucose (13).…”