Gossypol, a phytochemical with BH3-mimetic property, sensitizes cultured thoracic cancer cells to Apo2 ligand/tumor necrosis factor–related apoptosis-inducing.

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Gossypol, a phytochemical with BH3-mimetic property, sensitizes cultured thoracic cancer cells to Apo2 ligand/tumor necrosis factor–related apoptosis-inducing ligand Wen-Shuz Yeow, PhD, Aris Baras, Alex Chua, Duc M. Nguyen, Shailen S. Sehgal, BS, David S. Schrump, MD, FACS, Dao M. Nguyen, MD, MS, FRCSC, FACS The Journal of Thoracic and Cardiovascular Surgery Volume 132, Issue 6, Pages 1356-1362.e2 (December 2006) DOI: 10.1016/j.jtcvs.2006.07.025 Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 The effect of gossypol on the viability of thoracic cancer cells and primary normal cells. Cells were treated with gossypol for 24 hours and cell viability was determined by MTT assay at 36 hours after the onset of drug treatment. Data are presented as means ± SEM of 4 independent experiments. NHBE, Normal human bronchial epithelia; NHEK, normal human epidermal keratinocyte; micM, micromoles per liter. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure 2A Gossypol sensitizes cancer cells but not primary normal cells to Apo2L/TRAIL-mediated cytotoxicity. Cells were treated with Apo2L/TRAIL, gossypol, or gossypol+Apo2L/TRAIL for 24 hours, and cell viability was assessed by MTT at 36 hours. Data are presented as means ± SEM of 4 independent experiments. NHBE, Normal human bronchial epithelia; micM, micromoles per liter. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure 2B Apo2L /TRAIL IC50 values of cultured cancer cells treated with either Apo2L/TRAIL alone or gossypol+Apo2L/TRAIL combinations. These values were estimated from the respective dose-response curves and used as indicators of cellular sensitivity to Apo2L/TRAIL. Data are presented as means ± SEM of 4 independent experiments; #P < .0001 and +P < .01 versus Apo2L/TRAIL alone by analysis of variance and Bonferroni pairwise analysis. micM, Micromoles per liter. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Profound and supra-additive induction of apoptosis by the gossypol+Apo2L/TRAIL combinations in representative cancer cell lines H460, H211, and TE12. This combination does not induce apoptosis in primary normal cells. Data are presented as means ± SEM of 4 independent experiments. G, Gossypol; NHBE, Normal human bronchial epithelia; TUNEL, terminal deoxynucleotidyltransferase–mediated dUTP nick-end labeling; micM, micromoles per liter. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Significant reduction of gossypol+Apo2L/TRAIL-mediated apoptosis by the general caspase inhibitor Z-VAD-fmk or the caspase 9 inhibitor Z-LEHD-fmk in H211 and TE12 cells. Representative data of 3 independent experiments with similar results are shown. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Overexpression of Bcl2 protects cancer cells against the profound gossypol+Apo2L/TRAIL-mediated cytotoxicity in TE2 and TE12 Bcl2-overexpressing stable transfectants. Vector control stable transfectants were equally susceptible to the cytotoxic effect of this drug combination (data not shown). Data are presented as means ± SEM of 4 independent experiments; #P < .001 between gossypol+Apo2L/TRAIL in parental cells versus in Bcl2-overexpressing stable transfectants. G, Gossypol; GFP, green fluorescent protein. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure E1 Gossypol-mediated induction of apoptosis. Cells were exposed to gossypol (5.0 or 10.0 μmol/L) for either 24 hours or 48 hours and harvested at 48 hours after the onset of gossypol treatment for quantitation of apoptosis using the TUNEL-based ApoBrdU assay. Data are presented as means ± SEM of 4 independent experiments, #P < .001 versus gossypol 5.0 μmol/L × 48 hours, +P < .01 versus gossypol 10.0 μmol/L × 24 hours, *P < .001 versus gossypol 5.0 μmol/L × 24 hours. G, Gossypol; TUNEL, terminal deoxynucleotidyltransferase–mediated dUTP nick-end labeling; micM, micromoles per liter. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure E2 The effect of the duration of gossypol+Apo2L/TRAIL treatment on gossypol-mediated reduction of Apo2L/TRAIL IC50 values in representative H211, H460, and TE12 cells. Cells were treated with gossypol+Apo2L/TRAIL combination for 12 hours, 24 hours, or 36 hours, and cell viability was quantified by MTT at 36 hours after the onset of Apo2L/TRAIL exposure. Data are presented as means ± SEM of 4 independent experiments; #P = .0061 by ANOVA with statistically significant difference (P < .01) only between gossypol+Apo2L/TRAIL 12 hours and 36 hours; **P = .071 and +P = .077 by ANOVA and P > .05 by Bonferroni pairwise analysis. G, Gossypol. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure E3 Supra-additive activation of caspases 9 and 3 specific proteolytic activity in H460, TE2, and TE12 cells treated with the gossypol+Apo2L/TRAIL combination. Cells were treated with gossypol (5.0 μmol/L), Apo2L/TRAIL (10 ng/mL for H460 cells or 20 ng/mL for TE2 and TE12 cells), or gossypol+Apo2L/TRAIL combination. Representative data of 3 independent experiments are shown here. G, Gossypol. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions

Figure E4 Abrogation of gossypol+Apo2L/TRAIL-mediated cytotoxicity by Z-VAD-fmk. Cells were treated with 24 hours of gossypol, Apo2L/TRAIL, or gossypol+Apo2L/TRAIL with or without prior exposure to Z-VAD-fmk (60 μm). Cell viability was determined by MTT 36 hours after the onset of drug exposure. Data are presented as means ± SEM of 4 independent experiments; #P < .0001, +P = .0006 between gossypol+Apo2L/TRAIL with and without Z-VAD-fmk. The Journal of Thoracic and Cardiovascular Surgery 2006 132, 1356-1362.e2DOI: (10.1016/j.jtcvs.2006.07.025) Copyright © 2006 The American Association for Thoracic Surgery Terms and Conditions