Thioridazine Sensitizes Esophageal Carcinoma Cell Lines to Radiotherapy-Induced Apoptosis In Vitro and In Vivo

Abstract

BackgroundRadiotherapy is one of the primary treatments for esophageal squamous cell carcinoma (ESCC). Identification of novel radio-sensitizing agents will improve the therapeutic outcome of radiotherapy. This study aimed to determine the radio-sensitizing effect of the antipsychotic agent thioridazine in ESCC and explored the underlying mechanisms.Material/MethodsECA-109 and TE-1 ESCC cells were treated with thioridazine and radiotherapy alone and in combination. Cell survival was measured by MTT assay. Cell cycle and apoptosis were monitored by flow cytometry. Western blot analysis was used to analyze the expression of phospho-PI3K, phosphor-AKT, phospho-mTOR, Caspase-3, Caspase-9, Bax, Bcl-2, Bal-xl, Bak, and p53. The xenograft mouse model was used to study the in vivo anticancer effect of thioridazine and irradiation.ResultsCombined treatment with thioridazine and irradiation significantly reduced viability of ESCC cells compared with thioridazine or irradiation treatment alone. Thioridazine and irradiation treatment induced G0/G1 phases cell cycle arrest through down-regulation of CDK4 and cyclinD1. In addition, thioridazine and irradiation treatment induced apoptosis through up-regulation of cleaved capase-3 and 9, as well as an increase in the expression of Bax and Bak and a decrease in the expression of Bcl-2 and Bcl-xl. Furthermore, thioridazine and irradiation treatment inhibited the PI3K-AKT-mTOR pathway and up-regulated the expression of p53. In xenograft mice, thioridazine and irradiation reduced ESCC tumor growth.ConclusionsThioridazine sensitizes ESCC cells to radiotherapy. Thioridazine may play a role in ESCC radiation therapy as a promising radiosensitizer.

Targeting Prostate Cancer, the ‘Tousled Way’

“…Consistently, the expression of several YAP-target genes (e.g., CTGF, Zeb1, Twist1) that drive EMT and invasiveness of these cells was suppressed in the NEK1-KO clones [24], and there was no apparent compensation from other NEKs, which are not reported to act on YAP [103]. We have also tested by qRT-PCR the expression of several of these genes in LNCaP and C2 cells treated with BIC+J54, but in that case, the main effect was a dramatic 70-fold increase in BAX [49], confirming an effect previously reported in response to PTHs treatment of cancer cells [104]. This suggests that any residual YAP switches to the YAP/P73 transcriptional complex that implements the apoptotic program in response to DNA damage [105].…”

Targeting Prostate Cancer, The ‘Tousled Way’

“…Consistently, the expression of several YAP-target genes (e.g., CTGF, Zeb1, Twist1) that drive EMT and invasiveness of these cells was suppressed in the NEK1-KO clones [103], and there was no apparent compensation from other NEKs, which are not reported to act on YAP [105]. We have also tested by qRT-PCR the expression of several of these genes in LNCaP and C2 cells treated with BIC+J54, but in that case, the main effect was a dramatic 70-fold increase in BAX [100], confirming an effect previously reported in response to PTHs treatment of cancer cells [106]. This suggests that any residual YAP switches to the YAP/P73 transcriptional complex that implements the apoptotic program in response to DNA damage [107].…”

<p>Raltitrexed Enhances the Antitumor Effect of Apatinib in Human Esophageal Squamous Carcinoma Cells via Akt and Erk Pathways</p>

“…Firstly, we selected two ESCC cell lines, KYSE-30 and TE-1, which expressed the vascular endothelial growth factor receptor, VEGFR-2. 20,21 As shown in Figure 1A, Western blot result indicated that VEGFR-2 was detected in both KYSE-30 and TE-1 cells, with the HUVEC cell line used as the positive control for VEGFR-2 expression. Next, we examined how apatinib and raltitrexed treatments change the proliferation capacity of KYSE-30 and TE-1 cells.…”