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

Slides:

Advertisements

Similar presentations

Inhibition of the mTOR and MAPK pathways in the treatment of osteosarcoma Kathleen M. Diehl, M.D. FACS Assistant Professor University of Michigan.

Advertisements

Cell and Molecular Biology Behrouz Mahmoudi Cell cycle 1.

Modulation of the Cellular Phenotype in Human Colon Adenocarcinoma Cells by Folic Acid and Polyamine Pools Nathan W. Sweeney, Julie A. Buckmeier, Christina.

Histone Deacetylation Danielle Herrmann 2013 Doctor of Pharmacy Candidate University of Kansas School of Pharmacy Midwest Cancer Care.

Isosteviol derivatives induced apoptosis in Human lung cancer via targeting MEK/MAPK pathway: An in vitro and in vivo study Ahmed M Malki 1,,PhD Stephen.

 Dr. Steven Grant  Dr. Roberto Rosato  Jorge Almenara  Stefanie Coe  Dr. Allison Johnson, HHMI Coordinator.

Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

HDAC6 : HDAC6 is a cytoplasmic enzyme that regulates many important biological processes. : HDAC6 has recently emerged as a tubulin deacetylase that has.

Inhibition of PDCD6 Induces Cell Proliferation and Reduces Apoptosis in Human Epithelial Ovarian Cancer Cells Yan Huang, Xiaohua Wu Department of Gynecology,

Dual Inhibition of Cdc7 and Cdk9 by PHA Suppresses Hepatocarcinoma Synergistically with 5-FU Xi Chen, MD, PhD Associate Professor, Zhejiang University.

Elucidate the mechanism of anticancer activity of Piper nigrum extract on colon cancer cell line Akila Prashant, MVSST Subbarao, Devananda D, Prashant.

(A) TRYPAN BLUE CELL VIABILITY ASSAY

Comprehensive Analysis of the Chemical Composition and In Vitro Cytotoxic Mechanisms of Pallines Spinosa Flower and Leaf Essential.

{Non Fuctional Ikkβ (canonical pathway)}

Cell Physiol Biochem 2014;33: DOI: /

Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects Chi Chen, Ah-Ng Tony Kong Trends in Pharmacological.

PI3K inhibition does not Effect the BH3 Profile of SW620 Cells

Introduction Conclusions

Fig. 3. Western blot analysis of cell cycle regulators reveals loss of at least one CDK inhibitor. 75 ug/lane of protein extracts were loaded onto 8%

The Combined Effects of Hematoporphyrin Monomethyl Ether-SDT and Doxorubicin on the Proliferation of QBC939 Cell Lines Lei Liang, Sheng Xie, Lin Jiang,

Ke Xu, Ph.D. Putuo Hospital and Cancer Institute,

Induction of apoptosis of lung and esophageal cancer cells treated with the combination of histone deacetylase inhibitor (trichostatin A) and protein.

The Autophagy Inhibitor Chloroquine Overcomes the Innate Resistance of Wild-Type EGFR Non-Small-Cell Lung Cancer Cells to Erlotinib Yiyu Zou, PhD, Yi-He.

Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase regulate induction of Mcl-1 and survival in glucocorticoid-treated human neutrophils

Dual Inhibition of PI3K/AKT and MEK/ERK Pathways Induces Synergistic Antitumor Effects in Diffuse Intrinsic Pontine Glioma Cells Y. Linda Wu, Uday Bhanu.

Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR- Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients.

Figure 1. Artemisinin derivatives inhibited EOC growth and arrested the cell cycle at the G2/M phase (A) SKOV3 and primary epithelial ovarian cancer (EOC)

Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor–κB and IκBα kinase in human multiple myeloma cells, leading to.

Nitin TELANG 1, Hareesh B NAIR 2, George YC WONG 3, 4

G protein–coupled estrogen receptor 1 agonist G-1 induces cell cycle arrest in the mitotic phase, leading to apoptosis in endometriosis Taisuke Mori,

Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase regulate induction of Mcl-1 and survival in glucocorticoid-treated human neutrophils

Droxinostat, a Histone Deacetylase Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cell Lines via Activation of the Mitochondrial Pathway and.

The Chemopreventive Effect of Tanacetum Polycephalum Against LA7-Induced Breast Cancer in Rats and the Apoptotic Effect of a Cytotoxic Sesquiterpene.

Small-molecule inhibitor QLT-0267 suppresses ILK activity and inhibits its downstream signaling. Small-molecule inhibitor QLT-0267 suppresses ILK activity.

Mechanisms of apoptosis and growth arrest by isothiocyanates.

Supplementary Fig. 1 Co-treatment inhibited Ki67 expression.

Enhancement of depsipeptide-mediated apoptosis of lung or esophageal cancer cells by flavopiridol: Activation of the mitochondria-dependent death-signaling.

Induction of apoptosis of lung and esophageal cancer cells treated with the combination of histone deacetylase inhibitor (trichostatin A) and protein.

Volume 29, Issue 3, Pages (March 2016)

Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase.

Volume 6, Issue 1, Pages (January 2014)

G protein–coupled estrogen receptor 1 agonist G-1 induces cell cycle arrest in the mitotic phase, leading to apoptosis in endometriosis Taisuke Mori,

The Autophagy Inhibitor Chloroquine Overcomes the Innate Resistance of Wild-Type EGFR Non-Small-Cell Lung Cancer Cells to Erlotinib Yiyu Zou, PhD, Yi-He.

Synergistic Cytotoxicity of Sorafenib with Busulfan and Nucleoside Analogs in Human FMS-like Tyrosine Kinase 3 Internal Tandem Duplications–Positive Acute.

SUPPLEMENTAL TABLE 1. Cell cycle profiles of HeLa cells treated

Philip A. Rascoe, MD, Xiaobo Cao, MD, Jonathan C. Daniel, MD, Steven D

AT-101, a Pan-Bcl-2 Inhibitor, Leads to Radiosensitization of Non-small Cell Lung Cancer Luigi Moretti, MD, Bo Li, MD, Kwang Woon Kim, PhD, Heidi Chen,

Inhibition of PI3K-AKT-mTOR Signaling Sensitizes Melanoma Cells to Cisplatin and Temozolomide Tobias Sinnberg, Konstantinos Lasithiotakis, Heike Niessner,

SOX4 Promotes Proliferative Signals by Regulating Glycolysis through AKT Activation in Melanoma Cells Wei Dai, Xinyuan Xu, Shuli Li, Jingjing Ma, Qiong.

Lovastatin Sensitizes Lung Cancer Cells to Ionizing Radiation: Modulation of Molecular Pathways of Radioresistance and Tumor Suppression Toran Sanli,

Dasatinib, a small molecule inhibitor of the Src kinase, reduces the growth and activates apoptosis in pre-neoplastic Barrett's esophagus cell lines:

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

A p34cdc2 survival checkpoint in cancer

Volume 6, Issue 1, Pages (January 2014)

Volume 22, Issue 2, Pages (February 2015)

Molecular Therapy - Methods & Clinical Development

Yu-Fen Wang1, Ya-Chi Chan1, Dar-Ren Chen1, 2, Hui-Yi Lin3

Volume 41, Issue 6, Pages (December 2004)

Protein expression profiling of small cell lung carcinoma treated with valproic acid (VPA) and VAC (mafosfamide, doxorubicin and vindesine). Protein expression.

Epithelial to Mesenchymal Transition in an Epidermal Growth Factor Receptor-Mutant Lung Cancer Cell Line with Acquired Resistance to Erlotinib Kenichi.

Fig. 3. Effects of Tec on IL-1β-induced apoptosis in chondrocytes.

Methotrexate restores the function of peripheral blood Treg cells in psoriasis vulgaris via CD73/AMPK/mTOR pathway Kexiang Yan1，Wen Xu2,#，Yike Huang1，Zhenghua.

Ultraviolet-B-Induced G1 Arrest is Mediated by Downregulation of Cyclin-Dependent Kinase 4 in Transformed Keratinocytes Lacking Functional p53 Arianna.

Mitotic catastrophe symptoms caused by curcumin are followed by apoptosis. Mitotic catastrophe symptoms caused by curcumin are followed by apoptosis. A.

LY induces cytotoxicity in hMECs via inhibition of Akt/p70S6K kinase activities. LY induces cytotoxicity in hMECs via inhibition of Akt/p70S6K.

Volume 23, Issue 4, Pages (April 2015)

The effects of HDAC2 knockdown on cell-cycle proteins.

RA-9 induces G2–M cell-cycle arrest and caspase-mediated apoptosis in ovarian cancer cells. RA-9 induces G2–M cell-cycle arrest and caspase-mediated apoptosis.

LY elicits hyperphosphorylation of Akt.

Quercetin induces autophagy, blocks cell cycle and activation of ERK and JNK signaling pathways participates in the G1 arrest in P39 cells. Quercetin induces.

Presentation transcript:

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

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; 696-697.

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

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

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

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.

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

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

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.

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.

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)

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.

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).

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.

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

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

Thank you for your attention!