Dataset Information

Antitumor effect of sikokianin C, a selective cystathionine ?-synthase inhibitor, against human colon cancer in vitro and in vivo.

ABSTRACT: Cystathionine ?-synthase (CBS) overexpression is related to the proliferation and migration of human colon cancers. Targeted therapy that inhibits CBS has achieved promising effects in colon cancer treatments, but no selective inhibitor of CBS is available. In our previous study, a natural biflavonoid compound, sikokianin C, was identified as a potent and selective inhibitor of CBS. However, the mode of action of this compound and its antitumor efficacy in vivo remain unknown. In the present study, we have demonstrated that sikokianin C selectively inhibits CBS activity in a competitive manner, and the five key residues involved in the binding of sikokianin C to the substrate channel of CBS protein were identified via a combination of molecular docking and site-directed mutagenesis. Additionally, we analyzed the antitumor efficacy of sikokianin C against human colon cancer cells in vitro and in vivo. Sikokianin C greatly suppressed the proliferation of HT29 colon cancer cells with an IC50 value of 1.6 ?M, and CBS is the target of sikokianin C in mammalian cells, as evidenced by CBS knockdown analyses. Moreover, sikokianin C induced the apoptosis of HT29 cancer cells in a dose dependent manner. Treating mice with sikokianin C dramatically reduced the tumor volume and the weight of the colon cancer xenograft in vivo. These results indicate that the selective CBS inhibitor sikokianin C can potentially be used for the treatment of colon cancer.

SUBMITTER: Niu W

PROVIDER: S-EPMC6072513 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Antitumor effect of sikokianin C, a selective cystathionine β-synthase inhibitor, against human colon cancer in vitro and in vivo.

Niu Weining W Chen Fei F Wang Jun J Qian Jing J Yan Shasha S

MedChemComm 20171116 1

Cystathionine β-synthase (CBS) overexpression is related to the proliferation and migration of human colon cancers. Targeted therapy that inhibits CBS has achieved promising effects in colon cancer treatments, but no selective inhibitor of CBS is available. In our previous study, a natural biflavonoid compound, sikokianin C, was identified as a potent and selective inhibitor of CBS. However, the mode of action of this compound and its antitumor efficacy in vivo remain unknown. In the pres ...[more]

PMID: 30108905

Similar Datasets

Project description:Targeting the VEGF/VEGF receptor (VEGFR) pathway has proved to be an effective antiangiogenic approach for cancer treatment. Here, we identified 6-((2-((3-acetamidophenyl)amino)pyrimidin-4-yl)oxy)-N-phenyl-1-naphthamide (designated herein as DW10075) as a novel and highly selective inhibitor of VEGFRs.In vitro tyrosine kinase activity was measured using ELISA, and intracellular signaling pathway proteins were detected by Western blot analysis. Endothelial cell proliferation was examined with CCK-8 assays, and tumor cell proliferation was determined with SRB assays. Cell migration, tube formation and rat aortic ring assays were used to detect antiangiogenic activity. Antitumor efficacy was further evaluated in U87-MG human glioblastoma xenograft tumors in nude mice receiving DW10075 (500 mg · kg(-1) · d(-1), po) for two weeks.Among a panel of 21 kinases tested, DW10075 selectively inhibited VEGFR-1, VEGFR-2 and VEGFR-3 (the IC50 values were 6.4, 0.69 and 5.5 nmol/L, respectively), but did not affect 18 other kinases including FGFR and PDGFR at 10 μmol/L. DW10075 significantly blocked VEGF-induced activation of VEGFR and its downstream signaling transduction in primary human umbilical vein endothelial cells (HUVECs), thus inhibited VEGF-induced HUVEC proliferation. DW10075 (1-100 nmol/L) dose-dependently inhibited VEGF-induced HUVEC migration and tube formation and suppressed angiogenesis in both the rat aortic ring model and the chicken chorioallantoic membrane model. Furthermore, DW10075 exhibited anti-proliferative activity against 22 different human cancer cell lines with IC50 values ranging from 2.2 μmol/L (for U87-MG human glioblastoma cells) to 22.2 μmol/L (for A375 melanoma cells). In U87-MG xenograft tumors in nude mice, oral administration of DW10075 significantly suppressed tumor growth, and reduced the expression of CD31 and Ki67 in the tumor tissues.DW10075 is a potent and highly selective inhibitor of VEGFR that deserves further development.

Project description:Hydrogen sulfide (H2S) has been proposed to exert pro- as well as anti-inflammatory effects in various models of critical illness. In this study, we compared bacterial lipopolysaccharide (LPS)?induced changes in inflammatory mediator production, indices of multiple organ injury and survival in wild?type (WT) mice and in mice with reduced expression of one of the three H2S?producing enzymes, cystathionine-?-lyase (CSE), cystathionine-?-synthase (CBS) or 3-mercaptopyruvate sulfurtransferase (3MST). Mice were injected intraperitoneally (i.p.) with LPS (10 mg/kg). After 6 h, the animals were sacrificed, blood and organs were collected and the following parameters were evaluated: blood urea nitrogen (BUN) levels in blood, myeloperoxidase (MPO) and malondialdehyde (MDA) in the lung, cytokine levels in plasma and the expression of the three H2S?producing enzymes (CBS, CSE and 3MST) in the spleen, lung, liver and kidney. LPS induced a tissue?dependent upregulation of some of the H2S?producing enzymes in WT mice (upregulation of CBS in the spleen, upregulation of 3MST in the liver and upregulation of CBS, CSE and 3MST in the lung). Moreover, LPS impaired glomerular function, as evidenced by increased BUN levels. Renal impairment was comparable in the CSE?/? and ?3MST mice after LPS challenge; however, it was attenuated in the CBS+/? mice. MPO levels (an index of neutrophil infiltration) and MDA levels (an index of oxidative stress) in lung homogenates were significantly increased in response to LPS; these effects were similar in the WT, CBS+/?, CSE?/? and ?3MST mice; however, the MDA levels tended to be lower in the CBS+/? and CSE?/? mice. LPS induced significant increases in the plasma levels of multiple cytokines [tumor necrosis factor (TNF)?, interleukin (IL)?1?, IL?6, IL?10, IL?12 and interferon (IFN)?] in plasma; TNF?, IL?10 and IL?12 levels tended to be lower in all three groups of animals expressing lower levels of H2S?producing enzymes. The survival rates after the LPS challenge did not show any significant differences between the four animal groups tested. Thus, the findings of this study indicate that a deficiency in 3MST does not significantly affect endotoxemia, while a deficiency in CBS or CSE slightly ameliorates the outcome of LPS-induced endotoxemia in vivo.

Dataset Information

Antitumor effect of sikokianin C, a selective cystathionine ?-synthase inhibitor, against human colon cancer in vitro and in vivo.

Publications

Antitumor effect of sikokianin C, a selective cystathionine β-synthase inhibitor, against human colon cancer <i>in vitro</i> and <i>in vivo</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets