Imipramine and promethazine induce the apoptotic cell death of SCLC cells through activation of caspase-3. Imipramine and promethazine induce the apoptotic.

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Imipramine and promethazine induce the apoptotic cell death of SCLC cells through activation of caspase-3. Imipramine and promethazine induce the apoptotic cell death of SCLC cells through activation of caspase-3. A, representative immunoblotting of cleaved caspase-3 (CC3) in mSCLC (Kp1) and hSCLC (H82) cells treated with 50 μmol/L imipramine for 12 hours. Karyopherin was used as a loading control. B, representative immunostaining of CC3 in tumor sections (white dashed lines) from Rb/p53/p130–mutant mice treated daily with saline, imipramine, and promethazine for 30 consecutive days. C, quantification of the percentage of CC3-positive cells per tumor area of saline- (n = 142 tumors from 10 mice), imipramine- (n = 153 tumors from 9 mice; P < 0.0001), and promethazine- (n = 103 from 6 mice; P < 0.0001) treated tumors. D and E, effects of the combined treatment of imipramine (50 μmol/L) and the pan-caspase inhibitor Z-VAD-FMK on the survival of mSCLC (D) and hSCLC (E) after 24 hours of treatment, as measured by the MTT viability assay. Values from three independent experiments are shown as the mean ± SEM. The paired t test was used to calculate the P values of imipramine-treated cells versus control dimethyl sulfoxide (DMSO)-treated cells and of imipramine-treated cells versus Z-VAD-FMK–treated cells combined with imipramine. The black bars represent the vehicle-treated cells normalized to 100%. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant. F, quantification of the percentage of mSCLC cells (Kp1 and Kp3) with low Ca2+ levels by FACS analysis of control untreated cells (Ctrl) and imipramine-treated cells at the times indicated. Values from three independent experiments for each cell line are shown as the mean ± SEM. An unpaired t test was used to calculate the P values of imipramine-treated cells versus the untreated control cells at the times indicated. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant. G, representative immunoblotting of p-c-Jun, total c-Jun, p-JNK, and total JNK in mSCLC cells (Kp1) treated with 50 μmol/L imipramine for the indicated times. Tubulin was used as a loading control. H, representative immunoblotting of p-c-Jun, total c-Jun, p-JNK, and total JNK in mSCLC cells (Kp1 and H82) and NSCLC cells (LKR13 and A549) treated with 50 μmol/L imipramine for 1 hour. Tubulin was used as a loading control. I, effects of the combined treatment of 50 μmol/L imipramine and 500 nmol/L of the JNK inhibitor SP600125 on mSCLC cells (Kp1) after 24 hours of treatment, as measured by the MTT viability assay. Values from three independent experiments are shown as the mean ± SEM. An unpaired t test was used to calculate the P values of imipramine-treated cells versus control DMSO-treated cells and of imipramine-treated cells versus SP600125-treated cells combined with imipramine. *, P < 0.05 and ***, P < 0.001. DAPI, 4′,6-diamidino-2-phenylindole. Nadine S. Jahchan et al. Cancer Discovery 2013;3:1364-1377 ©2013 by American Association for Cancer Research