Dataset Information

Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC.

ABSTRACT: Glutaminase 1 (GLS1) expression is increased in non-small cell lung cancer (NSCLC). GLS1 knockdown using siRNA or inhibition using bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) induced cell cycle arrest with significant reduction of ATP level while levels of reactive oxygen species or glutathione were not affected in NSCLC cell lines. Recently we found that NSCLC significantly depends on cytosol NADH for ATP production. GLS1 remarkably contributes to ATP production through transferring cytosolic NADH into mitochondria via malate-aspartate shuttle by supply of glutamate in NSCLC. Regulation of malate-aspartate shuttle by knockdown or inhibition of glutamic-oxaloacetic transaminase 2 or malate dehydrogenase 2 mimicked GLS1 knockdown, which induced cell death with ATP reduction in NSCLC. Therefore, GLS1 inhibition induced cell cycle arrest with ATP depletion by glutamate reduction. Dual inhibition with BPTES and thymidylate synthase inhibitor, 5-fluorouracil (5-FU), elicits cell death synergistically through cell cycle arrest in NSCLC. A preclinical xenograft model of NSCLC showed remarkable anti-tumour effect synergistically in the BPTES and 5-FU dual therapy group.

SUBMITTER: Lee JS

PROVIDER: S-EPMC5261012 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC.

Lee Jae-Seon JS Kang Joon H JH Lee Seon-Hyeong SH Hong Dongwan D Son Jaekyoung J Hong Kyeong M KM Song Jaewhan J Kim Soo-Youl SY

Cell death & disease 20161208 12

Glutaminase 1 (GLS1) expression is increased in non-small cell lung cancer (NSCLC). GLS1 knockdown using siRNA or inhibition using bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) induced cell cycle arrest with significant reduction of ATP level while levels of reactive oxygen species or glutathione were not affected in NSCLC cell lines. Recently we found that NSCLC significantly depends on cytosol NADH for ATP production. GLS1 remarkably contributes to ATP production through ...[more]

PMID: 27929535

Similar Datasets

Project description:IntroductionThe development of a new type of Thymidylate synthase (TS) inhibitor that could inhibit cancer cells' proliferation and anti-angiogenesis is of great significance for cancer's clinical treatment.ObjectivesOur research hopes to develop a TS inhibitor that is more effective than the current first-line clinical treatment of pemetrexed (PTX) and provide a new reference for the clinical treatment of non-small cell lung cancer (NSCLC).MethodsWe obtained a series of novel TS inhibitors by chemical synthesis. Moreover, TS assay and molecular docking to verify the target compound's inhibitory mode. Use MTT assay, colony-forming assay, flow cytometry, and western blot to verify the compound's inhibitory effect on cancer cell proliferation and its mechanism; and explore the compound's effect on angiogenesis in vitro and in vivo. Further, explore the hit compound's anti-cancer ability through the xenograft tumor model and the orthotopic cancer murine model.ResultsA series of N-(3-(5-phenyl-1,3,4-oxadiazole-2-yl) phenyl)-2,4-dihydroxypyrimidine-5-sulfamide derivatives were synthesized as TS inhibitors for the first time. All target compounds significantly inhibited hTS enzyme activity and demonstrated significant antitumor activity against five cancer cell lines. Notably, 7f had a high selectivity index (SI) and unique inhibitory effects on eight NSCLC cells. In-depth research indicated that 7f could induce apoptosis by the mitochondrial pathway in A549 and PC-9 cells through the upregulation of wild-type P53 protein expression. Additionally, 7f was shown to inhibit angiogenesis in vitro and in vivo. In vivo studies, compared to PTX, 7f significantly inhibited tumor growth in A549 cell xenografts and had a higher therapeutic index (TGI). Moreover, 7f could prolong the survival of the orthotopic lung cancer murine model more effectively than PTX.ConclusionThe anti-angiogenic effect of 7f provides a new reference for the development of TS inhibitors and the clinical treatment of NSCLC.

Dataset Information

Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC.

Publications

Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets