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. 2017 Jul 20;8(12):2256-2262.
doi: 10.7150/jca.19566. eCollection 2017.

Development of a new analog of SGK1 inhibitor and its evaluation as a therapeutic molecule of colorectal cancer

Xuchun Liang  1 , Chunling Lan  2 , Jinzhe Zhou  3 , Wencheng Fu  1 , Xuesha Long  1 , Yu An  2 , Guanming Jiao  1 , Kejin Wang  1 , Yongqin Li  1 , Jiahong Xu  4 , Qi Huang  3 , Bin Xu  2 , Junjie Xiao  1
Affiliations

Development of a new analog of SGK1 inhibitor and its evaluation as a therapeutic molecule of colorectal cancer

Xuchun Liang et al. J Cancer. .

Abstract

Colorectal cancer (CRC) is one of the most leading causes of cancer-related death worldwide. The serum and glucocorticoid inducible kinase SGK1 is highly expressed and involved in several tumors. GSK650394, a SGK1 inhibitor, has been proved to be effective in impeding tumor growth in vitro. In this study, we developed a novel analog of GSK650394, and evaluated its effects on CRC cells and tumor growth both in vitro and in vivo. HCT116 cells were treated with a concentration gradient of new developed compounds and cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 value of every analog. Cell proliferation analysis was estimated from EdU staining and flow cytometry in vitro, and immunohistochemistry of Ki67 and PCNA in vivo. Cell migration analysis was examined using the transwell assay. In vivo tumor growth was determined in athymic nude mice by injecting the HCT116 cells in the subcutaneous tissue, followed by the injection of QGY-5-114-A. We found that new developed GSK650394 analog QGY-5-114-A has lower IC50 value, and treatment with QGY-5-114-A significantly inhibited CRC cell proliferation and migration in vitro. Besides that, colonic tumor growth was also dramatically restricted by QGY-5-114-A in vivo. In conclusion, pharmacological treatment with QGY-5-114-A impedes CRC tumor cell proliferation, migration and tumor growth.

Keywords: Cell migration; Cell proliferation; Colonic tumor growth; Colorectal cancer; Inhibitor; Serum and glucocorticoid inducible kinase 1.

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Conflict of interest statement

Competing Interests: The authors declare no competing financial interests.

Figures

Fig 1
Fig 1
Chemical structure of GSK650394 and 39 new developed analogs.
Fig 2
Fig 2
Seven compounds of the 39 newly developed GSK650394 analogs suppress cell viability. (A) Cell viability analysis of HT116 cells treated with 50 μM GSK650394 and 39 new analogs, as determined by CCK-8 assay. (B) Cell viability analysis of HT116 cells treated with various concentrations of compounds.
Fig 3
Fig 3
QGY-5-114-A inhibits HCT116 cell proliferation. (A) EdU staining of HCT116 cells and EdU-positive cell proportion. Scale bar, 100 μm; n = 4; ***, P<0.001; (B) HCT116 cell cycle analysis by flow cytometry. ***, P<0.001.
Fig 4
Fig 4
QGY-5-114-A inhibits HT29 cell proliferation. (A) EdU staining of HT29 cells and EdU-positive cell proportion. Scale bar, 100 μm; n=4; ***, P<0.001; (B) Cell cycle analysis of HT29 cells by flow cytometry. ***, P<0.001.
Fig 5
Fig 5
QGY-5-114-A suppresses the migration of HCT116 cells. Decrease in HCT116 cell numbers after migration for 48 hours by QGY-5-116, n=4; Scale bars, 100 μm; ***, P<0.001.
Fig 6
Fig 6
QGY-5-114-A restrains tumor growth and cell proliferation in subcutaneous xenograft mice model. (A) The procedure of establishing the xenotransplant mice model. (B) Transplanted tumor size of control and mice injected with QGY-5-114-A. n=4; (C) Transplanted tumor volume. n=4; (D) Reduction in Ki67- and PCNA-positive cell populations in skin tissues treated with QGY-5-114-A. Scale bars, 200 μm; *, P<0.05;
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