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A novel class I histone deacetylase inhibitor, I-7ab,

A novel class I histone deacetylase inhibitor, I-7ab, induces apoptosis and arrests cell cycle progression in human colorectal cancer cells. Kecheng Lei Mentor: Prof.Jianwen Liu State Key Laboratory of Bioreactor Engineering Shanghai Key Laboratory of New Drug Design

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A novel class I histone deacetylase inhibitor, I-7ab,

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  1. A novel class I histone deacetylase inhibitor, I-7ab, induces apoptosis and arrests cell cycle progression in human colorectal cancer cells Kecheng Lei Mentor: Prof.Jianwen Liu State Key Laboratory of Bioreactor Engineering Shanghai Key Laboratory of New Drug Design East China University of Science and Technology Shanghai, PR China 2016.08.09

  2. 1. 1. The trend of cancer deaths worldwide. BACKGROUND 11.4 million 10 million .2030 9 million .2020 7.6 million .2015 6 million .2006 .2002 • Richard Ha; American Journal of Roentgenology. 2014;202; 696-697.

  3. BACKGROUND 1.2. Biological functions of HDACs. • Li Z; Int J Biol Sci 2014;10:757–70.

  4. BACKGROUND 1.3. HATs and HDACs modify histones and proteins . • GlozakMA, Oncogene 2007;26:5420–32.

  5. BACKGROUND 1.4. HDAC family members control hallmarks of cancer cell biology. • Witt O; Cancer Lett 2009;277:8–21.

  6. BACKGROUND 1.5. Small molecule inhibitors of epigenetic enzymes that have entered human clinical trials. • Copeland RA; Curr Opin Chem Biol 2010;14:505–10.

  7. RESULTS 2.1. Chemical structures of I-7ab. Figure . Chemical structures of I-7ab.

  8. RESULTS 2.2. I-7ab exhibited cytotoxicity toward diverse human cancer cells Figure . I-7ab displayed antitumor activity.

  9. RESULTS 2.3. I-7ab inhibited the expression of HDAC3 and other class I HDACs in HCT116 cells . Figure . HDAC expression analysis after treatment with I-7ab. (A) Western blot analysis for the indicated HDACs after treatment with 0, 0.25, 0.5, 1and2μM inHCT116 cells;（B）Proteins from HCT116 cells treated withI-7ab (2 μM) for 0, 24, 36, 48, 72 h were analyzed using western blotting. β-actin was used as aloading control.

  10. RESULTS 2.4. X-ray crystal structure and Docking studies of HDAC 3. Figure . X-ray crystal structure of HDAC3 and bound inhibitor showing H-bonding to asp-101. Docking studies of HDAC 3 showing potential for H-bonding to asp-99 from the bioisoteric imidazole.

  11. RESULTS 2.5. I-7ab induced apoptosis of HCT116 cells Figure . I-7ab induced apoptosis in HCT116 cells. Flow cytometry analyses determined the apoptosis of cells treated with various concentrations of I-7ab for 48 h (A and B) and cells treated with 2 mM I-7ab for various times (C and D)

  12. RESULTS 2.5. I-7ab induced apoptosis of HCT116 cells Figure. Cell apoptosis induced by different dose of I-7ab was further confirmed by Hoechst 33258 staining and comet assays.

  13. RESULTS 2.6. I-7ab arrested cell cycle progression of HCT116 cells via downregulating cyclin B1-CDK1 complex Figure. Flow cytometry analyses determined DNA content in HCT116 cells treated with different concentrations of I-7ab for 48 h (A and B), and cells treated with 2 mM I-7ab for different times ( C and D).

  14. RESULTS 2.7. I-7ab altered the expression of related proteins. Figure. I-7ab arrested cell cycle progression and altered the expression of apoptosis and cell cycle related proteins. I-7ab downregulated Bcl-2 and cyclin B1, upregulated Bax, p53, and p21, and suppressed the translocation of NF-kB, EGFR, and suppressing the phosphorylation of downstream ERK and AKT in HCT116 cells.

  15. CONCLUSION HDACI (HDAC3) EGFR AKT NF-kB PI3K P53 P21 CyclinB1 G2/M transition Mitochondrial apoptosis

  16. Acknowledgement Prof. Jianwen Liu Prof. Weiping Deng Liyan Yang Qiannan Liang Ke Shen Li Ma Na An

  17. Thank you for your attention!

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