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.
Highlights
Activity were measured by in vitro Lactate dehydrogenase A (LDHA) assay using purified recombinant human LDHA
The result showed that PSTMB, 1-methyl-4-phenylselenobenzene, 1-methoxy-4-(phenylseleno)benzene, 4-(phenylseleno)-1,1′-biphenyl, tetrahydro-3-(phenylseleno) thiophene, and 1-methoxy-4-[(phenylmethyl)seleno]benzene had inhibitory effects on LDHA activity
These active compounds have not been reported as Pan Assay Interference Compounds (PAINS)[17]
Summary
Oxamate (50 mM) was used as the positive control for LDHA inhibition. Data were statistically compared using the Student’s t-test. ***p < 0.001 compared to the positive control (2nd column). ***p < 0.001 compared to the negative control (1st column). ###p < 0.001 compared with the control (2nd column). Among various selenobenzenes that we tested, we found that 1-(phenylseleno)-4-(trifluoromethyl)benzene (PSTMB) has the most potent inhibitory effect on LDHA. The molecular mechanism underlying the LDHA inhibition and anti-tumor activity was investigated. From these results, we suggest that PSTMB can be a novel candidate for anti-tumor drug development by regulating cancer metabolism
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