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

2. Richard Ha; American Journal of Roentgenology. 2014;202; 696-697.
BACKGROUND
1. 1. The trend of cancer deaths worldwide.
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;

3. 1.2. Biological functions of HDACs.
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. Copeland RA; Curr Opin Chem Biol 2010;14:505–10.
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. Figure . Chemical structures of I-7ab.
RESULTS
2.1. Chemical structures of I-7ab.
Figure . Chemical structures of I-7ab.

8. Figure . I-7ab displayed antitumor activity.
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 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. Mitochondrial apoptosis
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!