Synergy between verapamil and other multidrug-resistance modulators in model membranes

Castaing, Madeleine; Loiseau, Alain; Cornish‐Bowden, Athel

doi:10.1007/s12038-007-0073-5

Cited by 10 publications

(11 citation statements)

References 32 publications

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“…This may explain the anti-CSC ability of THIO that was discovered through small-molecule library screening (26,34). A previous study has indicated that THIO could reverse chemoresistance of cancer cells and achieve a significant therapeutic outcome in combination therapy with verapamil (35). A recent study also demonstrated that the combination of THIO and doxorubicin using polymeric micelles might provide a promising strategy for breast cancer treatment by targeting both cancer cells and cancer stem cells (16).…”

Section: Discussionmentioning

confidence: 98%

Thioridazine elicits potent antitumor effects in colorectal cancer stem cells

et al. 2016

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As a member of the phenothiazine family, thioridazine (THIO) is a potent anti-anxiety and anti-psychotic drug. Recent studies have reported that THIO could suppress the growth of several types of cancer cells. However, the effect of THIO on colorectal cancer stem cells (CSCs) has not been investigated. In the present study, we examined the effect of THIO on viability of CSCs isolated from the human colon cancer cell line HCT116 and its colony-formation ability, along with its stem cell-specific gene expression. The CSCs, EpCAM+ and CD44+ subpopulations from HCT116 cells were isolated using immunomagnetic beads. After incubation with several concentrations of THIO, we evaluated the proliferation and invasion ability of colon CSCs, as well as cell apoptosis. We found that THIO significantly suppressed the proliferation and invasion of colon CSCs and induced cell apoptosis in a concentration-dependent manner. The expression of some apoptosis genes (Bax and caspase-3) was upregulated after treatment with THIO, while that of the anti-apoptosis gene Bcl-2 was downregulated. Moreover, the CSC mitochondrial membrane potential was downregulated. Overall, this study showed that THIO inhibits the proliferation of CSCs derived from the HCT116 cell line through induction of apoptosis, and thus, could be a promising agent for the treatment of colon cancer and worthy of exploring in prospective clinical studies.

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Section: Discussionmentioning

confidence: 98%

Thioridazine elicits potent antitumor effects in colorectal cancer stem cells

et al. 2016

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“…Thioridazine was previously found to reverse the chemoresistance of cancer cells, and a significant therapeutic outcome in combination with verapamil was noted (11). Thus, thioridazine may be considered as an adjuvant in combination with chemotherapeutic drugs for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Thioridazine was also able to reverse the chemoresistance of human KB carcinoma cells by increasing the accumulation of chemotherapeutic drugs doxorubicin, vinblastine and dactinomycin in the cells (10). Thioridazine in combination with verapamil exhibited enhanced ability to reverse the multidrug resistance of cancer cells (11). Moreover, thioridazine was found to inhibit the expression of P-glycoprotein and induce the apoptosis of ABCB1-overexpressing drug-resistant mouse lymphoma (12,13).…”

Section: Introductionmentioning

confidence: 99%

Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer

et al. 2014

Oncology Reports

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Abstract. Thioridazine, an antipsychotic drug, has been reported to induce apoptosis in various types of cancer cells, with specificity on targeting cancer stem cells (CSCs). However, whether it elicits anticancer effects in gastric cancer has never been reported. In the present study, we examined the ability of thioridazine to induce cell death in the gastric cancer cell lines NCI-N87 and AGS, and detected its in vivo tumor inhibition capacity. Thioridazine elicited cytotoxic effects on NCI-N87 and AGS cells in a dose-dependent manner, and inhibited the colony formation abilitiy of the NCI-N87 and AGS cells. Thioridazine treatment induced nuclear fragmentation, increased the proportion of sub-G1 phase cells, and elevated the percentage of Annexin V-positive cells, suggesting the occurrence of apoptosis. Moreover, thioridazine induced gastric cancer cell apoptosis in a caspase-dependent manner, as shown by a decrease in the precursors of casapse-9, caspase-8 and caspase-3, and by the ability of the caspase inhibitor Z-VAD-FMK to reverse the cytotoxic effect of thioridazine. JC-1 staining further revealed that thioridazine induced gastric cancer cell apoptosis via the mitochondrial pathway. In addition, thioridazine pretreatment inhibited the growth of NCI-N87 cell-derived tumors. The present study demonstrated that the antipsychotic drug thioridazine possesses anti-gastric cancer ability through in vitro and in vivo experiments, suggesting thioridazine as a potential drug in gastric cancer therapy. IntroductionGastric cancer is the fourth most common cancer worldwide with 989,600 new cases diagnosed in 2008, and it is the second leading cause of cancer-related death (1,2). Gastric cancer is either asymptomatic or causes non-specific symptoms at an early stage, and thus the majority of patients present with advanced stage disease at the time of initial diagnosis, leading to the poor prognosis of gastric cancer. Gastric cancer treatment involves surgery, chemotherapy, radiation therapy and their combinations. However, current drugs are confronted with low efficacy due to the high rate of patients at the advanced stage of gastric cancer. Thus, the development of novel effective drugs for gastric cancer therapy is urgently needed.Thioridazine, an antagonist of the dopamine receptor D2 family proteins, was initially developed as an antipsychotic drug, and recently its anticancer function was revealed. Studies have revealed the antiproliferative and apoptosis induction capacities of thioridazine in neuroblastoma, glioma, leukemia, breast cancer, cervical cancer and endometrial cancer (3-6). A gene signature-based approach identified thioridazine as an inhibitor of PI3K/Akt signaling in ovarian cancer cells. It downregulated cell cycle regulators cyclin D1 and CDK4, and upregulated p21, p16 and p-CDC25A, leading to the G0/ G1 phase arrest of the cells (7). Research on cervical and endometrial cancer cells disclosing the involvement of the PI3K/Akt/mTOR pathway in thioridazine-induced apoptosis further supported this fi...

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“…Recently, it has been reported that thioridazine suppresses cancer cell growth by inhibiting proliferation, inducing apoptosis, and regulating the activity of the anti-apoptosis signaling pathway [ 10 – 14 ]. Thioridazine can significantly enhance the anti-proliferative activity of doxorubicin in treating breast cancer cells and cancer stem cell-like cells, which shows that thioridazine has significant chemo-sensitizing ability [ 26 , 27 ]. Moreover, thioridazine can increase the TRAIL-mediated apoptosis via the ROS mediated inhibition of Akt signaling and down-regulation of Mcl-1 and c-FLIP(L) [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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

Xia

Wang

et al. 2016

Med Sci Monit

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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.

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Synergy between verapamil and other multidrug-resistance modulators in model membranes

Cited by 10 publications

References 32 publications

Thioridazine elicits potent antitumor effects in colorectal cancer stem cells

Thioridazine elicits potent antitumor effects in colorectal cancer stem cells

Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer

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

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