A novel action mechanism for MPT0G013, a derivative of arylsulfonamide, inhibits tumor angiogenesis through up-regulation of TIMP3 expression

Chih-Ya, Wang,; Liou, Jing Ping; Tsai, An-Chi; Lai, Mei-Jung; Liu, Yimin; Lee, Hsueh Yun; Wang, Jing-Chi; Pan, Shiow Lin; Chen, Teng

doi:10.18632/oncotarget.2451

Cited by 12 publications

(11 citation statements)

References 32 publications

(32 reference statements)

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“…Abnormal expression of DNMT3B is related to the hypermethylation of the tumor suppressor genes. TIMP3 is an inhibitor of extracellular matrix metalloproteinase that can suppress angiogenesis [ 41 , 42 ], tumor growth [ 43 , 44 ], and invasion and migration [ 43 – 45 ]. It has been reported that in many common tumors, CpG islands of TIMP3 undergo methylation frequently [ 46 , 47 ] and that in the primary tumors, the methylation of the TIMP3 promoter can lead to the loss of its protein expression [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway

Wan

Zheng

et al. 2018

Clin Epigenet

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BackgroundmiR-29c has been associated with the progression of many cancers. However, the function and mechanism of miR-29c have not been well investigated in breast cancers.MethodsReal-time quantitative PCR was used to assess expression of miR-29c and DNMT3B mRNA. Western blot and immunochemistry were used to examine the expression of DNA methyltransferase 3B (DNMT3B) protein in breast cancer cells and tissues. The functional roles of miR-29c in breast cancer cells such as proliferation, migration, invasion, colony formation, and 3D growth were evaluated using MTT, transwell chambers, soft agar, and 3D Matrigel culture, respectively. In addition, the luciferase reporter assay was used to check if miR-29c binds the 3′UTR of DNMT3B. The effects of miR-29c on the DNMT3B/TIMP3/STAT1/FOXO1 pathway were also examined using Western blot and methyl-specific qPCR. The specific inhibitor of STAT1, fludarabine, was used to further check the mechanism of miR-29c function in breast cancer cells. Studies on cell functions were carried out in DNMT3B siRNA cell lines.ResultsThe expression of miR-29c was decreased with the progression of breast cancers and was closely associated with an overall survival rate of patients. Overexpression of miR-29c inhibited the proliferation, migration, invasion, colony formation, and growth in 3D Matrigel while knockdown of miR-29c promoted these processes in breast cancer cells. In addition, miR-29c was found to bind 3′UTR of DNMT3B and inhibits the expression of DNMT3B, which was elevated in breast cancers. Moreover, the protein level of TIMP3 was reduced whereas methylation of TIMP3 was increased in miR-29c knockdown cells compared to control. On the contrary, the protein level of TIMP3 was increased whereas methylation of TIMP3 was reduced in miR-29c-overexpressing cells compared to control. Knockdown of DNMT3B reduced the proliferation, migration, and invasion of breast cancer cell lines. Finally, our results showed that miR-29c exerted its function in breast cancers by regulating the TIMP3/STAT1/FOXO1 pathway.ConclusionThe results suggest that miR-29c plays a significant role in suppressing the progression of breast cancers and that miR-29c may be used as a biomarker of breast cancers.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0495-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway

Wan

Zheng

et al. 2018

Clin Epigenet

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“…In our previous findings, we investigated the arylsulfonamide derivative MPT0G013 as a potent inhibitor of antiangiogenic activities by activating 14, 15. The literature survey indicates that hydroxamic acid contributes to the histone deacetylase (HDAC) inhibition activity through interfering with the binding mode of zinc ion at the catalytic site, and it becomes the symbolic moiety of HDAC inhibitors 16-18.…”

Section: Introductionmentioning

confidence: 99%

TIMP3 expression associates with prognosis in colorectal cancer and its novel arylsulfonamide inducer, MPT0B390, inhibits tumor growth, metastasis and angiogenesis

et al. 2019

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Tissue inhibitors of metalloproteinase 3 (TIMP3) are a major endogenous inhibitor of matrix metalloproteinase (MMPs) that inhibit tumor growth, invasion, metastasis and angiogenesis. In this study, we found that TIMP3 expression is associated with positive prognosis of colorectal cancer (CRC) clinicopathologically. Therefore, we developed a series of arylsulfonamide derivatives as TIMP3 inducers in order to define potential colorectal cancer therapeutic agent. Among these, MPT0B390 was selected for anti-tumor, anti-metastasis, and anti-angiogenesis property determination.Methods: The relationship between TIMP3 expression and clinical pathological features in colorectal patients and cell lines were determined by immunohistochemistry, bioinformatics analysis and western blotting. The anti-tumor function was validated by using MTT, apoptosis pathway detection and in vivo xenograft model for tumor growth inhibition determination. The anti-metastatic function was validated using a transwell migration assay, and using in vivo lung metastasis and liver metastasis models. The mechanism of MPT0B390-induced TIMP3 expression was further tested using qPCR and Chromatin IP assay. The anti-angiogenesis function was examined by using transwell migration assay, and in vivo Matrigel plug assay.Results: After screening candidate compounds, we identified MPT0B390 as an effective inducer of TIMP3. We showed that MPT0B390 induces TIMP3 expression significantly and inhibits CRC cell growth in vitro and in vivo. By inducing TIMP3 expression, MPT0B390 can also exert its anti-metastasis effect to inhibit CRC cell migration and invasion and downregulates migration markers such as uPA, uPAR, and c-Met. Subsequent Chromatin immunoprecipitation assay revealed that MPT0B390 can significantly inhibit EZH2 expression as well as its binding to TIMP3 promoter region to regulate TIMP3 induction. In addition to the anti-tumor and anti-metastasis capability, MPT0B390 can also induce TIMP3 expression in endothelial cells to inhibit tumor angiogenesis.Conclusion: These data suggest the potential therapeutic applications of the TIMP3 inducer, MPT0B390, for colorectal cancer treatment.

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“…Recently, HDAC inhibitors are considered as a new type of anti-cancer therapeutics, which show promising results in pre-clinical studies and early phase clinical trials. MPT0G013, a novel HDAC inhibitor, was reported by our colleague to inhibit tumor angiogenesis through up-regulation of TIMP3 expression [ 31 ]. The GI 50 values of MPT0G013 on Hep3B cells and HUVECs are 0.36 μM and 0.14 μM, respectively [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…MPT0G013, a novel HDAC inhibitor, was reported by our colleague to inhibit tumor angiogenesis through up-regulation of TIMP3 expression [ 31 ]. The GI 50 values of MPT0G013 on Hep3B cells and HUVECs are 0.36 μM and 0.14 μM, respectively [ 31 , 32 ]. In the present study, we observed that MPT0G009 exhibits greater potency on cancer cells than HUVECs with the IC 50 values of 0.75 μM and 7.61 μM, respectively.…”

Section: Discussionmentioning

confidence: 99%

Novel histone deacetylase inhibitor MPT0G009 induces cell apoptosis and synergistic anticancer activity with tumor necrosis factor-related apoptosis-inducing ligand against human hepatocellular carcinoma

et al. 2015

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Hepatocellular carcinoma (HCC) is a frequent cause of cancer-related death; therefore, more effective anticancer therapies for the treatment of HCC are needed. Histone deacetylase (HDAC) inhibitors serve as promising anticancer drugs because they can induce cell growth arrest and apoptosis. We previously reported that 3-[1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]-N-hydroxyacrylamide (MPT0G009)—a novel 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines compound—demonstrated potent pan-HDAC inhibition and anti-inflammatory effects. In this study, we evaluated the anti-HCC activity of MPT0G009 in vitro and in vivo. Growth inhibition, apoptosis, and inhibited HDAC activity induced by MPT0G009 were more potent than a marketed HDAC inhibitor SAHA (Vorinostat). Furthermore, MPT0G009-induced apoptosis of Hep3B cells was characterized by an increase in apoptotic (sub-G1) population, loss of mitochondrial membrane potential, activation of caspase cascade, increased levels of pro-apoptotic protein (Bim), and decreased levels of anti-apoptotic proteins (Bcl-2, Bcl-xL, and FLICE-inhibitory protein); the downregulation FLIP by MPT0G009 is mediated through proteasome-mediated degradation and transcriptional suppression. In addition, combinations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with lower concentrations (0.1 μM) of MPT0G009 were synergistic in cell growth inhibition and apoptosis in HCC cells. In the in vivo model, MPT0G009 markedly reduced Hep3B xenograft tumor volume, inhibited HDAC activities, and induced apoptosis in the Hep3B xenografts. Our results demonstrate that MPT0G009 is a potential new candidate drug for HCC therapy.

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A novel action mechanism for MPT0G013, a derivative of arylsulfonamide, inhibits tumor angiogenesis through up-regulation of TIMP3 expression

Cited by 12 publications

References 32 publications

miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway

miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway

TIMP3 expression associates with prognosis in colorectal cancer and its novel arylsulfonamide inducer, MPT0B390, inhibits tumor growth, metastasis and angiogenesis

Novel histone deacetylase inhibitor MPT0G009 induces cell apoptosis and synergistic anticancer activity with tumor necrosis factor-related apoptosis-inducing ligand against human hepatocellular carcinoma

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