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The antitumor mechanism of Desmosdumotin C Analog

ABSTRACT: In our continuing study of the desmosdumotin C (1) series, twelve new analogues, 21–32, mainly with A-ring modifications, were prepared and evaluated for in vitro anticancer activity against several human tumor cell lines. Among them, the 4′-iodo-3,3,5-tripropyl-4-methoxy analogue (31) showed significant cytotoxicity against multiple human tumor cell lines with ED50 values of 1.1–2.8 microM. Elongation of the C-3 and C-5 carbon chains reduced activity relative to propyl substituted analogues; however, activity was still better than that of natural 1. Among analogues with various ether groups on C-4, compounds with methyl (2) and propyl (26) ethers inhibited cell growth of multiple tumor cells lines, while 28 with an iso-butyl ether showed selective cytotoxicity against lung cancer A549 cells (ED50 1.7 microM). The gene expression profiles showed that 3 may modulate the spindle assembly checkpoint (SAC) and chromosome separation, and thus, arrest cells at the G2/M-phase. We used microarrays to elucidate the underlying antitumor mechanism induced by Desmosdumotin C Analog Analogue 3 showed potent cytotoxicity against the highly invasive non-small-cell lung cancer cell line CL1-5 with an ED50 value of 0.11 µM. To determine which genes were differentially expressed upon CL1-5 treatment with analogue 3, the genome-wide mRNA expression profiles of 3-treated cells and control cells were determined using Affymetrix human genome U133 plus 2.0 GeneChip according to the Manufacturer’s protocols

ORGANISM(S): Homo sapiens

SUBMITTER: Yu Sung-Liang

PROVIDER: S-ECPF-GEOD-24584 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BackgroundFucoidan, a water-soluble polysaccharide, exerts anticoagulant and antiviral functions. It was recently reported that fucoidan also exerts an antitumor function. Lung cancer is one of the most common cancers in the world. The aim of this study was to investigate anti-tumor,apoptosis and anti-metastasis effects of fucoidan in both cell-based assays and mouse xenograft model, as well as to clarify possible role of m-TOR pathway in the protection.MethodsIn vitro: Different concentrations of fucoidan were given to act on non-small cell lung cancer (NSCLC) cell lines A549 and H1650. The effects of fucoidan on cell proliferation were observed by detecting cyclin expression levels, CCK8 and EDU experiments and cloning experiments. The apoptotic level was detected by flow cytometry and the apoptotic protein level was detected by Westernblot. By detecting the expression of adhesion molecules, the expression of matrix metalloproteinase (MMP) family, and Transwell cell invasion and migration experiment, the effect of fucoidan on cell adhesion, invasion and migration was observed. Meanwhile the effect of fucoidan on angiogenesis was observed by detecting the expression of vascular endothelial growth factor (VEGF). In vivo experiment: An animal model of NSCLC cell mouse subcutaneous xenograft tumor was established to analyze the correlation between the consumption of fucoidan and the size and volume of xenograft tumor through gross observation. Through immunohistochemical staining and immunofluorescence double staining, ki67 and cell adhesion molecules (E-cadherin, N-cadherin and CD31) and VEGF-A in the tumor were detected, and the correlation between the amount of fucoidan and the above indexes was analyzed.ResultsFucoidan inhibited the proliferation and angiogenesis of NSCLC cells via the mTOR pathway and promoted their apoptosis by increasing the Bax/Bcl-2 ratio. Not only that, fucoidan inhibited NSCLC cell invasion via epithelial-mesenchymal transformation (EMT). The mice fed fucoidan exhibited significant reductions in tumor volumes and weights. These indicators (Ki67, VEGF-A,N-cadherin) were decreased and E-cadherin expression was up-regulated in A549 mice that treated with fucoidan. The results showed that fucoidan inhibited tumor proliferation in vivo by affecting the expression of related proteins.ConclusionFucoidan conveys antitumor effects and our results represent an ideal therapeutic agent for NSCLC.

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The antitumor mechanism of Desmosdumotin C Analog

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