A Novel Lactate Dehydrogenase Inhibitor, 1-(Phenylseleno)-4-(Trifluoromethyl) Benzene, Suppresses Tumor Growth through Apoptotic Cell Death

Abstract

The Warburg effect, wherein cancer cells prefer glycolysis rather than oxidative phosphorylation even under normoxic conditions, is a major characteristic of malignant tumors. Lactate dehydrogenase A (LDHA) is the main enzyme regulating the Warburg effect, and is thus, a major target for novel anti-cancer drug development. Through our ongoing screening of novel inhibitors, we found that several selenobenzene compounds have inhibitory effects on LDHA activity. Among them, 1-(phenylseleno)-4-(trifluoromethyl) benzene (PSTMB) had the most potent inhibitory effect on the enzymatic activity of LDHA. The results from biochemical assays and computational modeling showed that PSTMB inhibited LDHA activity. In addition, PSTMB inhibited the growth of several tumor cell lines, including NCI-H460, MCF-7, Hep3B, A375, HT29, and LLC. In HT29 human colon cancer cells, PSTMB dose-dependently inhibited the viability of the cells and activity of LDHA, without affecting the expression of LDHA. Under both normoxic and hypoxic conditions, PSTMB effectively reduced LDHA activity and lactate production. Furthermore, PSTMB induced mitochondria-mediated apoptosis of HT29 cells via production of reactive oxygen species. These results suggest that PSTMB may be a novel candidate for development of anti-cancer drugs by targeting cancer metabolism.

Synthesis and initial screening of lactate dehydrogenase inhibitor activity of 1,3-benzodioxole derivatives

“…Compound 10, a benzothiazole compound harboring a -CF 3 moiety, could also be considered as a potential LDHA inhibitor. Although higher IC 50 in vitro LDHA assay, the GI 50 value of compound 10 is lower than that of previously reported selenobenzene compound, 1-(phenylseleno)-4-(trifluoromethyl) benzene 18 . The GI 50 value of compound 10 in PANC-1 cells is comparable to that of standard compounds, GSK2837808A and GNE140.…”

“…In vitro evaluation on LDHA inhibitor activity. LDHA activity assay was performed in accordance with previous studies 16,18 . Briefly, the various concentrations of compounds were incubated with reaction buffer containing 20 mM HEPES-K + , 20 μM NADH, 2 mM pyruvate, and 100 ng of purified recombinant human LDHA protein (Abcam, Cambridge, UK).…”

“…Intracellular LDHA activity assay. To observe the LDH activities from the lysates of cells, we performed in accordance with previous studies 16,18 . Briefly, Total protein from lysate (1 μg) was mixed with containing 20 mM HEPES-K + , 20 μM NADH, 2 mM pyruvate.…”

The future of cancer immunotherapy: microenvironment-targeting combinations

“…155 MCT1 inhibition, using AZD3965, is currently under phase I investigation (NCT01791595). LDHA inhibitors, which mediate lactate production, are an exciting new class of agents that have demonstrated preclinical efficacy, 156 and we expect to see clinical development of these drugs.…”

Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets

“…Drugs to inhibit LDH enzymatic activity are being examined. PSTMB induces apoptosis of lung cancer, breast cancer, colon cancer, and melanoma cells via LDH inhibition [ 256 ]. FX-11, galloflavin, and gossypol have anticancer effects via LDH inhibition [ 257 , 258 ].…”