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

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Droxinostat, a Histone Deacetylase Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cell Lines via Activation of the Mitochondrial Pathway and Downregulation of FLIP Jing Liu, Guangming Li, Xiang Wang, Liang Wang, Rui Zhao, Juanxia Wang, Yin Kong, Jie Ding, Juan Li, Lingyi Zhang Translational Oncology Volume 9, Issue 1, Pages 70-78 (February 2016) DOI: 10.1016/j.tranon.2016.01.004 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Droxinostat inhibits cell proliferation and colony formation in HepG2 and SMMC-7721 cells. (A, D) MTT assay illustrating cell proliferation (0 to 120 hours) following treatment with various concentrations of droxinostat in HepG2 (A) and SMMC-7721 (D) cells. Data are expressed as absorbance values (490 nm), compared with untreated control cells. (B, E) The Real-time cell viability analysis ( RTCA RT-CES SP) system, another cell proliferation method, shown the following 96-hour treatment with various concentrations of droxinostat added at 24 hours in HepG2 (b) and SMMC-7721 (E) cells. Data are expressed as CI, compared with untreated control cells. (C, F) Number of colonies in HepG2 (C) and SMMC-7721 (F) cells after treatment with 20 μM droxinostat at 15 days. Results are expressed as number of colonies, compared with the control group (mean ± SE) (*P < .05, **P < .01). Translational Oncology 2016 9, 70-78DOI: (10.1016/j.tranon.2016.01.004) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Droxinostat suppresses HDAC3 expression and acetylates histones H3 and H4. HepG2 (A) and SMMC-7721(B) cells were cultured with 0, 10, 20, or 40 μM droxinostat for 48 hours. Western blot analysis using antibodies against HDAC3, Ac-H3, and Ac-H4 was performed after 48-hour incubation with droxinostat. Internal reference protein loading was verified via the detection of β-actin. (B, D, F, H) Protein expression, expressed as relative content, was examined using Gray analysis and compared with that in the control group (mean ± SE) (*P < .05, **P < .01). Translational Oncology 2016 9, 70-78DOI: (10.1016/j.tranon.2016.01.004) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Droxinostat induces HepG2 cell apoptosis by activating the mitochondrial apoptotic pathway and downregulating expression of FLIP. (A) Apoptotic cells were determined via flow cytometry following staining with Annexin V and PI. (B) Apoptosis rates of HepG2 cells treated with different concentrations of droxinostat were analyzed using bar graphs. (C) mRNA levels of genes related to the mitochondrial p53 apoptosis pathway were analyzed using qRT-PCR. (D) Levels of proteins associated with the mitochondrial p53 apoptosis pathway were analyzed via Western blot. (E) The relative contents of proteins of the mitochondrial p53 apoptosis pathway were analyzed using bar graphs. (F) Bax/Bcl-2 protein ratio. (G) Protein levels related to FLIP and caspase-8 were analyzed via Western blot. (H) Relative FLIP and caspase-8 levels were analyzed using bar graphs. Data are shown as means ± SE of three independent experiments, *P < .05, **P < .01, compared with untreated control cells (no droxinostat). Translational Oncology 2016 9, 70-78DOI: (10.1016/j.tranon.2016.01.004) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Droxinostat induces apoptosis in SMMC-7721 cells by activating the mitochondrial apoptotic pathway and downregulating FLIP. (A) Apoptotic cells were determined via flow cytometry following staining with Annexin V and PI. (B) Apoptosis rates of SMMC-7721 cells treated with different concentrations of droxinostat were analyzed using bar graphs. (C) mRNA levels of genes related to the mitochondrial p53 apoptosis pathway were analyzed using qRT- PCR. (D) Levels of proteins associated with the mitochondrial p53 apoptosis pathway were analyzed via Western blot. (E) Relative contents of proteins from the mitochondrial p53 apoptosis pathway were analyzed using bar graphs. (F) Bax /Bcl-2 protein ratio. (G) Protein levels of FLIP and caspase-8 were analyzed via Western blot. (H) Relative contents of FLIP and caspase-8 were analyzed using bar graphs. Data are presented as means ± SE of three independent experiments, *P < .05, **P < .001, compared with untreated control cells (no droxinostat). Translational Oncology 2016 9, 70-78DOI: (10.1016/j.tranon.2016.01.004) Copyright © 2016 The Authors Terms and Conditions

Figure 5 Knockdown of HDAC3 induces hepatoma cell apoptosis and acetylation of histones H3 and H4. A: Data obtained with HepG2 cells. (A) Apoptotic populations of HepG2 HDAC3-silenced cells determined via flow cytometry. (B) Analysis of apoptosis rates using bar graphs. (C) HDAC3 protein is downregulated by siRNA against HDAC3 in HepG2 cells. (D, E) Expression of cleaved PARP and cleaved caspase 3 proteins is significantly increased upon knockdown of HDAC3 in HepG2 cells. (F, G) Expression of Ace-H3 and Ace-H4 proteins is significantly increased upon knockdown of HDAC3 in HepG2 cells. B: Data obtained with SMMC-7721 cells. (H) Apoptotic population of SMMC-7721 HDAC3-silenced cells determined via flow cytometry. (I) Analysis of apoptosis rates using bar graphs. (J) HDAC3 is downregulated by siRNA against HDAC3 in SMMC-7721 cells. (H, L) Expression of cleaved caspase 3 is significantly increased upon knockdown of HDAC3 in SMMC-7721 cells. (M, N) Expression of Ace-H3 and Ace-H4 proteins is significantly increased upon knockdown of HDAC3 in SMMC-7721 cells. Translational Oncology 2016 9, 70-78DOI: (10.1016/j.tranon.2016.01.004) Copyright © 2016 The Authors Terms and Conditions