DCT015, a new sorafenib derivate, inhibits tumor growth and angiogenesis in gastric cancer models
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The objective of this study is to investigate antiproliferative activities against gastric cancer and anti-angiogenesis of DCT015, a novel sorafenib derivate, and potential mechanisms. The effects of DCT015 on proliferation and apoptosis in gastric cancer cells were evaluated by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blotting assays. The in vivo antitumor effects were carried out in nude mice bearing gastric cancer. On the other hand, the anti-angiogenesis effects of DCT015 were measured by human umbilical vein endothelial cell (HUVEC) proliferation, migration, tube formation, and Western blotting analysis. The results showed that DCT015 inhibited the proliferation, induced the morphological changes of apoptosis, and increased the apoptosis percentage, as well as increased the “sub-G1” population in gastric cancer cells. DCT015 also significantly decreased the tumor volumes and tumor weights in vivo by oral administration. Immunohistochemistry assay demonstrated that DCT015 inhibited tumor growth and neovascularization. In vitro studies found that DCT015 inhibited both MEK/ERK and PI3K/Akt signaling pathways by Western blotting assays. Moreover, DCT015 significantly inhibited VEGF-induced migration and tube formation in HUVECs. Western blotting analysis showed that DCT015 downregulated VEGF-induced VEGFR2 phosphorylation with the decreased phosphorylation of the downstream key proteins. Taken together, our findings highlight that DCT015 is a promising orally anticancer drug for treating gastric cancer.
KeywordsDCT015 Sorafenib Proliferation Angiogenesis Apoptosis Targeted therapy
We thank Nanjing Luye Sike Pharmaceuticals for providing the compounds. Shandong Luye Pharmaceutical Co. Ltd. is gratefully acknowledged for providing some experiment conditions including the laboratory and some reagents.
This work was supported by the National Natural Science Foundation of China (no. 81001661), the Shandong Province Young and Middle-Aged Scientists Research Awards Fund (no. BS2009SW012), the National Basic Research Program of China (no. 2012CB724003), the Natural Science Foundation of Shandong Province, China (no. ZR2014HM091), and the Scientific Research Foundation of Binzhou Medical College, Shandong Province, China (no. BY2013KYQD21).
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Conflict of interest
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