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Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer.

ABSTRACT: Combination chemotherapy is a potentially promising approach to enhance anticancer activity, overcome drug resistance, and improve disease-free and overall survival. The current study investigates the antitumor activity of sodium dichloroacetic acid (DCA) in combination with SIRT2 inhibitor Sirtinol and AGK2. We found that combining DCA with Sirtinol produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model. Synergistic potentiation of oxidative phosphorylation (OXPHOS) was observed, including decreased glucose consumption, decreased lactate production, increased OCR and increased ROS generation, possibly via co-targeting pyruvate dehydrogenase alpha 1(PDHA1). Mechanically, AGK2 and Sirtinol were found to increase the lysine-acetylation and decrease the serine-phosphorylation of PDHA1, which enabled the two inhibitors to synergize with DCA to further activate PDHA1. Besides, a AMPKα-ROS feed-forward loop was notably activated after the combined treatments compared with mono-therapy. Our results indicate that the combination of DCA and SIRT2 inhibitor may provide a promising therapeutic strategy to effectively kill cancer cells.

SUBMITTER: Ma W

PROVIDER: S-EPMC6154844 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer.

Ma Wenjing W Zhao Xiaoping X Wang Kaiying K Liu Jianjun J Huang Gang G

Cancer biology & therapy 20180801 9

Combination chemotherapy is a potentially promising approach to enhance anticancer activity, overcome drug resistance, and improve disease-free and overall survival. The current study investigates the antitumor activity of sodium dichloroacetic acid (DCA) in combination with SIRT2 inhibitor Sirtinol and AGK2. We found that combining DCA with Sirtinol produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model. Synergistic potentiation of ...[more]

PMID: 30067423

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Project description:BackgroundAcute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML.MethodsThe up-regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used.ResultsThrough bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small-molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS-5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS-5584 induced apoptosis and cycle arrest of AML cells in a dose- and time-dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS-5584 treatment, with 287 proteins being down-regulated and 71 proteins being up-regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS-5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS-5584 caused a significant reduction in the half-maximal inhibitory concentration (IC50 ) of VS-5584 on AML cells. In vivo, experiments suggested that VS-5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein.ConclusionsTaken together, the PI3K/mTOR inhibitor VS-5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

Dataset Information

Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer.

Publications

Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer.

Similar Datasets

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