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

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Induction of apoptosis of lung and esophageal cancer cells treated with the combination of histone deacetylase inhibitor (trichostatin A) and protein kinase C inhibitor (calphostin C) Justin B. Maxhimer, BA, Rishindra M. Reddy, MD, Jingtong Zuo, MD, George W. Cole, MD, David S. Schrump, MD, FACS, Dao M. Nguyen, MD, FRCSC, FACS The Journal of Thoracic and Cardiovascular Surgery Volume 129, Issue 1, Pages 53-63 (January 2005) DOI: 10.1016/j.jtcvs.2004.07.051 Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 A, Growth-inhibitory effects of TSA on the NSCLC cells H322 and H460 and the EsC cells TE2 and TE12. Cell viability was quantitated by means of MTT assay and expressed as percentages of untreated control cells. Data are presented as means ± SEM of 4 independent experiments. B, TSA dose-dependent induction of cell growth arrest at the G0/G1 or G2/M phases of the cell cycle. Cultured cancer cells were treated with normal media and either 0.1 μmol/L or 5.0 μmol/L TSA for 12 hours and then further cultured in TSA-free complete culture media. Cells were harvested at 12 hours after completion of drug treatment, and cell-cycle analysis was performed by using propidium iodide staining and flow cytometry. Representative data of 3 independent experiments that yielded similar results are shown. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 53-63DOI: (10.1016/j.jtcvs.2004.07.051) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Induction of apoptosis by TSA treatment of the NSCLC cells H460 and H322 and the EsC cells TE2 and TE12. Cells were exposed to TSA (0.5-5.0 μmol/L) for either 12 or 24 hours and then harvested at 48 hours for determination of apoptosis with the TUNEL-based ApoBrdU assay and flow cytometry. Data are presented as means ± SEM of 4 independent experiments. #P = .004 to .046, Student t test between 12-hour and 24-hour treatment groups. *P = .0079 to .013, analysis of variance with Tukey-Kramer multiple comparison tests between TSA of 1, 2, and 5 μmol/L and TSA of 0.5 μmol/L. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 53-63DOI: (10.1016/j.jtcvs.2004.07.051) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 A, Profound inhibition of TSA-mediated upregulation of p21 promotor activity and NF-κB transcriptional activity by the PKC inhibitor CC in all NSCLC and EsC cells. Data are presented as folds of increase of luciferase activity over activity of untreated control cells (means ± SEM of 4 independent experiments). B, Inhibition of TSA-mediated upregulation of p21 levels by the PKC inhibitor CC. Protein levels of p21 in lysates of treated cells were quantitated by means of enzyme-linked immunosorbent assay. The levels were normalized for total cellular protein and then expressed as fold changes over levels of untreated control cells. Data are presented as means ± SEM of 4 independent experiments. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 53-63DOI: (10.1016/j.jtcvs.2004.07.051) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Western blot analysis of the effect of TSA alone and the TSA+CC combination on proapoptotic, antiapoptotic, and NF-κB–dependent proteins. Increased induction of antiapoptotic proteins is seen in treatment with TSA alone and in the proapoptotic protein, with little to no change in the combination treatment. However, abrogation of the antiapoptotic proteins is seen in the TSA+CC combination. Representative data from 2 independent experiments with comparable results are shown. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 53-63DOI: (10.1016/j.jtcvs.2004.07.051) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 A, Synergistic inhibition of cell proliferation by the TSA+CC combinations in representative NSCLC H322 cells and EsC TE12 cells. Cells were treated with TSA (0.1-5.0 μmol/L) for 12 hours, followed by a replacement with drug-free culture media (TSA treatment alone) or culture media containing CC (0.25, 0.5, and 1.0 μmol/L; TSA+CC combinations). B, The TSA+CC combination effect was also examined in primary human fibroblasts and human umbilical vein endothelial cells, respectively. Cell viability was determined by using the MTT assay 60 hours after completion of TSA treatment. Dose-response curves of cells treated with the TSA+CC combinations were constructed by normalizing for the mild growth-inhibitory effect of CC treatment alone. Data are presented as means ± SEM of 4 independent experiments. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 53-63DOI: (10.1016/j.jtcvs.2004.07.051) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 6 Profound induction of apoptosis of NSCLC H322 and H460 cells or EsC TE2 and TE12 cells by the combinations of TSA and CC. Cells were treated with TSA alone (1.0 μmol/L for 12 hours), CC alone (1.0 μmol/L continuous exposure), or TSA followed by continuous CC. Cells were harvested at 48 hours after the onset of treatment to assay for apoptosis. Data are presented as means ± SEM of 4 independent experiments. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 53-63DOI: (10.1016/j.jtcvs.2004.07.051) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions

Figure 7 A, Selective inhibition of NF-κB transcriptional activity by the adenoviral vector expressing IκB (AdV-SR-IκB) or the pharmacologic NF-κB inhibitor parthenolide not only results in profound abrogation of TSA-mediated NF-κB activation but also the TSA-mediated upregulation of p21 gene transcription. Cells were transiently transfected with either the NF-κB–luciferase plasmid or the p21 promotor–luciferase plasmid before further treatment with AdV-SR-IκB (200 pfu/cell), parthenolide (20 nmol/L), and TSA (0.1 or 1.0 μmol/L). Data are presented as folds of increase of luciferase activity over activity of untreated control cells (means ± SEM of 4 independent experiments). B, Induction of apoptosis of H322 and TE12 by AdV-SR-IκB–infected cells in combination with TSA. Both AdV-SR-IκB–infected cells and vector control cells were treated with TSA (1.0 μmol/L for 12 hours) and harvested 12 hours later for quantitation of apoptosis by using the TUNEL-based ApoBrdU assay. Representative data of 3 independent experiments are shown. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 53-63DOI: (10.1016/j.jtcvs.2004.07.051) Copyright © 2004 The American Association for Thoracic Surgery Terms and Conditions