Machilin A Inhibits Tumor Growth and Macrophage M2 Polarization Through the Reduction of Lactic Acid

Chung, Tae‐Wook; Kim, Eun-Yeong; Han, Chang Woo; Park, So Young; Jeong, Mi Suk; Yoon, Dahye; Choi, Hee‐Jung; Park, Mi-Ju; Kwon, Yun Ju; Lee, Hanna; Kim, Keuk‐Jun; Park, Kang Hyun; Kim, Suhkmann; Jang, Se Bok; Ha, Ki‐Tae

doi:10.3390/cancers11070963

Cited by 36 publications

(30 citation statements)

References 54 publications

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“…The compound 10 is a moderate perpetrator of drug-drug interactions based on their inhibition of the most abundant CYP450 enzymes, such as 1A2 and 2C19. The compound 2 exhibits a simple structure with one 1,3-benzodioxole group compared to the previously reported Machilin A 16 , containing two 1,3-benzodioxole groups. Furthermore, it has a lower LDHA IC 50 value compared to Machilin A (84 µM).…”

Section: Resultsmentioning

confidence: 66%

“…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.…”

Section: Synthesis Of Compound 10mentioning

confidence: 99%

“…These compounds include 1,3-benzodioxole derivatives, such as Machilin A (Fig. 1 ), which are efficient competitive inhibitors that function by blocking the nicotinamide adenine dinucleotide (NAD) binding site of LDHA, suppressing lactate production and cancer cell growth 16 . Furthermore, benzodioxole ring-containing thiazolyl-pyrazoline derivatives were tested against MCF-7 and B16-F10 tumor cells and showed significant antiproliferative activity in vitro 17 .…”

Section: Introductionmentioning

confidence: 99%

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

Annas

Cheon²,

Yusuf

et al. 2020

Sci Rep

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Cancer is one of the main causes of mortality in the world. Many cancer cells produce ATP through high-level lactic acid fermentation catalyzed by lactate dehydrogenase (LDH), which converts pyruvic acid to lactic acid. LDH plays a dominant role in the Warburg effect, wherein aerobic glycolysis is favored over oxidative phosphorylation. Due to the high lactic acid production level in cancer cells, LDH-targeting could be a potential cancer treatment strategy. A few approaches, such as drug treatment, reportedly inhibited LDH activity. In this study, we describe new 1,3-benzodioxole derivatives that might be potential small molecule candidates for LDHA inhibition. The synthesis was carried out by trans-esterification between aryl ester and alcohol groups from piperonyl alcohol. Compounds 2 and 10 exhibited a selective LDHA IC50 value of 13.63 µM and 47.2 µM, respectively. Whereas only compound 10 showed significant cytotoxicity in several lines of cancer cells, especially in human pancreatic cancer PANC-1 cells. These synthesized compounds possess 2 aromatic rings and –CF3 moiety, which expectedly contributes to LDHA inhibition. The presented products have the potential to become a promising LDHA inhibitor drug candidate.

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Section: Resultsmentioning

confidence: 66%

Section: Synthesis Of Compound 10mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Annas

Cheon²,

Yusuf

et al. 2020

Sci Rep

Self Cite

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show abstract

“…Based on the crystal structures, the allosteric transition by the activator within two subunits is not required for the LDHB activity. Recently, machilin A (MA) has been reported to bind to LDHA in an interfacial allosteric site close to the FBP binding site 27 . However, its binding conformation of MA remains controversial because steric clashes of the protein-ligand interactions have been observed.…”

Section: Discussionmentioning

confidence: 99%

Identification of the First Highly Selective Inhibitor of Human Lactate Dehydrogenase B

Shibata¹,

Sogabe²,

Miwa³

et al. 2020

Preprint

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Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+ and has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To our knowledge, selective inhibitors for LDHB have yet to be reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD+. The screening campaign identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. It exhibited uncompetitive LDHB inhibition (IC50 = 42 nM). X-ray crystallography identified its binding with the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerization interface of the two dimers is critical for enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.

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“…LDHA (lactate dehydrogenase A) is a vital enzyme responsible for cancer growth and energy metabolism via the aerobic glycolytic pathway. Inhibition of LDHA could inhibit tumor-initiating cell survival and proliferation, which indicated that LDHA may be a potential therapeutics target [27]. GK1 (phosphoglycerate kinase 1) is an important enzyme in the metabolic glycolysis pathway.…”

Section: Discussionmentioning

confidence: 99%

Screening hypoxia-related genes as prognostic biomarkers and modeling the individualized prognostic predictor in hepatocellular carcinoma

Guo

Zhang

et al. 2019

Preprint

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Background Hypoxia closely relates to malignant progression and appears to be prognostic for outcome in hepatocellular carcinoma (HCC). Our research aims to mine the Hypoxic related genes (HRGs) on the role of clinical prognosis in HCC. Moreover, we construct and define a model of prognostic predictor (PP) to estimate and improve prognosis of HCC patients.Results 37 differentially expressed HRGs were obtained. It contained 28 up-regulated and 9 down-regulated genes. After the univariate Cox regression model analysis, we obtained 27 prognosis-related HRGs. Of these, 25 genes were risk factors for cancer and 2 genes were protective factors. The PP was composed of the 10 key genes (HDLBP, SAP30, PFKP, DPYSL4, SLC2A1, PGK1, ERO1A, LDHA, ENO2, TPI1), and significantly divided patients of HCC into high- and low-risk groups according to overall survival (OS) ( P <0.001). We got the Area Under Curve(AUC) value of risk score calculated by PP was 0.777, which much bigger than other clinical parameters. Besides, PP was verified as an independent prognosis-related parameter (in univariate analyse, HR=1.484, 95% CI=1.342–1.642, P<0.001; in multivariate analyse, HR=1.414, 95% CI=1.258–1.588, P <0.001). Finally, the application of PP in clinic was concluded that the higher the patient's risk score, the higher the corresponding tumor stage and T stage, and the patient's prognosis was poor.Conclusions This study provides hypoxic related molecular targets for the therapeutic intervention. In addition, an individualized prognostic predictor was constructed to predict prognosis for HCC patients .

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Machilin A Inhibits Tumor Growth and Macrophage M2 Polarization Through the Reduction of Lactic Acid

Cited by 36 publications

References 54 publications

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

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

Identification of the First Highly Selective Inhibitor of Human Lactate Dehydrogenase B

Screening hypoxia-related genes as prognostic biomarkers and modeling the individualized prognostic predictor in hepatocellular carcinoma

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