Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine

Yue, Haiying; Huang, Dongning; Qin, Li; Zheng, Zhiyong; Li, Hua; Wang, Guodong; Huang, Jian; Huang, Haixin

doi:10.1155/2016/6709828

Cited by 35 publications

(30 citation statements)

References 20 publications

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“…Thioridazine induces apoptosis [3] , [4] , [5] , [6] , [7] , [8] as well as inhibits angiogenesis [9] , [10] and metastasis [11] in cancer cells. Furthermore, thioridazine induced stem cell differentiation to overcome neoplastic self-renewal [12] as well as inhibited sphere formation of stem cells and decreased the stemness [13] . Several molecular mechanisms of anti-cancer effects of thioridazine have been known.…”

Section: Introductionmentioning

confidence: 99%

NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

Seo

Kim

et al. 2017

Redox Biology

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Thioridazine is known to have anti-tumor effects by inhibiting PI3K/Akt signaling, which is an important signaling pathway in cell survival. However, thioridazine alone does not induce apoptosis in head and neck squamous cell carcinoma (AMC-HN4), human breast carcinoma (MDA-MB231), and human glioma (U87MG) cells. Therefore, we investigated whether combined treatment with thioridazine and curcumin induces apoptosis. Combined treatment with thioridazine and curcumin markedly induced apoptosis in cancer cells without inducing apoptosis in human normal mesangial cells and human normal umbilical vein cells (EA.hy926). We found that combined treatment with thioridazine and curcumin had synergistic effects in AMC-HN4 cells. Among apoptosis-related proteins, thioridazine plus curcumin induced down-regulation of c-FLIP and Mcl-1 expression at the post-translational levels in a proteasome-dependent manner. Augmentation of proteasome activity was related to the up-regulation of proteasome subunit alpha 5 (PSMA5) expression in curcumin plus thioridazine-treated cells. Combined treatment with curcumin and thioridazine produced intracellular ROS in a NOX4-dependent manner, and ROS-mediated activation of Nrf2/ARE signaling played a critical role in the up-regulation of PSMA5 expression. Furthermore, ectopic expression of c-FLIP and Mcl-1 inhibited apoptosis in thioridazine and curcumin-treated cells. Therefore, we demonstrated that thioridazine plus curcumin induces proteasome activity by up-regulating PSMA5 expression via NOX4-mediated ROS production and that down-regulation of c-FLIP and Mcl-1 expression post-translationally is involved in apoptosis.

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Section: Introductionmentioning

confidence: 99%

NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

Seo

Kim

et al. 2017

Redox Biology

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“…The 95-D human cell line is a highly invasive and metastatic lung carcinoma cell line (19). It has been found that 95-D cells cultured in specific medium can be used to accumulate lung cancer stem-like cells in spheres, which are called lung cancer stem cells (LCSCs) (20). Thus, we investigated the role of NELL1 in 95-D cancer stem-like cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Human 95-D cells are highly invasive and metastatic lung cancer cells (19). In previous research, cultured in specific medium, 95-D cells can be used to accumulated lung cancer stem cells in spheres, which were called LCSCs (20). Conventional and traditional therapies that fail to eradicate CSCs may reduce tumor cells temporarily; however, resistance, metastasis and relapse are more likely to occur when treatment is suspended.…”

Section: Effect Of Nell1 On Lung Cancer Stem-like Cell Differentiationmentioning

confidence: 99%

Effect of NELL1 on lung cancer stem‑like cell differentiation

Zhai

Wei²,

Sha

et al. 2019

Oncol Rep

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The cancer stem cell theory recently has received enormous attention in cancer biology. Lung cancer stem-like cells are a subpopulation of undifferentiated lung tumor cells critical for lung cancer tumorigenesis, metastasis and resistance to therapy and disease relapse. The neural EGFL like 1 (NELL1) is a potent growth factor believed to preferentially target cells committed to the osteochondral lineage; yet, its expression and function in lung cancer are largely unknown. In the present study, we used specific medium to accumulate lung cancer stem-like cells of 95-D cells in spheres and obtained these highly expressed CD133 cells through flow cytometric cell sorting of CD133-stained cells which were termed 95-D lung cancer stem-like cells (95-D LCSCs). These 95-D LCSCs highly expressed stemness genes CD133, Oct4 and Sox2 determined by western blot analysis and quantitative real-time polymerase chain reaction (qPCR) analysis. Notably, we found that overexpression of NELL1 significantly reduced colony formation and invasion of 95-D LCSCs tested by soft agar colony formation and cell invasion assay. In addition, as determined by cell proliferation assay, overexpression of NELL1 increased the chemotherapeutic sensitivity of 95-D LCSCs to carboplatin and cisplatin. NELL1 also reduced the expression of phospho-MET (p-MET), Notch3 and HES1, which suggests that NELL1 may induce 95-D LCSC differentiation by inhibiting the expression of c-MET-Notch signaling. Our results suggest that NELL1 induces lung cancer stem-like cell differentiation, which provides a new potential therapeutic target for cancer stem cells.

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“…First, the anti-proliferative activity of thioridazine takes place at high concentrations to ensure intercalation of the compound between nucleic bases [ 4 ]. Thioridazine could dramatically inhibit sphere formation of lung cancer stem cells [ 12 ] and elicited cytotoxic effects on the gastric cancer cell lines [ 5 ] in a dose-dependent manner. However, thioridazine was mainly prescribed as a low-potency antipsychotic drug in clinical practice, its use was limited due to multiple side effects, for example, somnolence, constipation, dry mouth, dose-related risk of QT prolongation and retinitis pigmentosa.…”

Section: Discussionmentioning

confidence: 99%

Association between Thioridazine Use and Cancer Risk in Adult Patients with Schizophrenia-A Population-Based Study

Chang

Hsieh

Wang

et al. 2018

Psychiatry Investig

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ObjectiveSeveral cell line studies have demonstrated thioridazine’s anticancer, multidrug resistance-reversing and apoptosis-inducing properties in various tumors. We conducted this nationwide population-based study to investigate the association between thioridazine use and cancer risk among adult patients with schizophrenia. MethodsBased on the Psychiatric Inpatient Medical Claim of the National Health Insurance Research Database of Taiwan, a total of 185,689 insured psychiatric patients during 2000 to 2005 were identified. After excluding patients with prior history of schizophrenia, only 42,273 newly diagnosed patients were included. Among them, 1,631 patients ever receiving thioridazine for more than 30 days within 6 months were selected and paired with 6,256 randomly selected non-thioridazine controls. These patients were traced till 2012/12/31 to see if they have any malignancy. ResultsThe incidence rates of hypertension and cerebrovascular disease were higher among cases than among matched controls. The incidence of hyperlipidemia, coronary artery disease and chronic pulmonary disease did not differ between the two groups. By using Cox proportional hazard model for cancer incidence, the crude hazard ratio was significantly higher in age, hypertension, hyperlipidemia, cerebrovascular disease, coronary artery disease and chronic pulmornary disease. However, after adjusting for other covariates, only age and hypertension remained significant. Thioridazine use in adult patients with schizophrenia had no significant association with cancer. ConclusionDespite our finding that thioridazine use had no prevention in cancer in adult patients with schizophrenia. Based on the biological activity, thioridazine is a potential anticancer drug and further investigation in human with cancer is warranted.

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Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine

Cited by 35 publications

References 20 publications

NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

Effect of NELL1 on lung cancer stem‑like cell differentiation

Association between Thioridazine Use and Cancer Risk in Adult Patients with Schizophrenia-A Population-Based Study

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