Thioridazine has potent antitumor effects on lung cancer stem-like cells

Abstract

Thioridazine (TDZ), originally an anti-psychotic drug, suppresses several types of cancer and has specificity for leukemia stem cells. The present study was performed to assess its effect on lung cancer stem-like cells, as its effect remains unknown. TDZ was utilized to treat lung cancer stem-like cells (A549 sphere cells) and its cytotoxic effect and mechanism were evaluated in vitro and in vivo. TDZ elicited cytotoxicity in A549 sphere cells and inhibited their proliferation in a dose-dependent pattern. A549 sphere cells treated with TDZ showed nuclear fragmentation, increased G0/G1 phase distribution, positive Annexin V staining, and a change in the expression of caspase family and cell cycle-associated proteins. These results suggest the induction of caspase-dependent apoptosis and cell cycle arrest. In addition, TDZ treatment resulted in significant inhibitory effect on mice xenografts established by A549 sphere cells. TDZ repressed growth of lung cancer stem-like cells in vitro and in vivo, indicating its potential application in targeting lung cancer stem-like cells.

Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors

“…Inhibition of the TLK1/NEK1 axis with thioridazine (THD), a rather specific inhibitor of TLKs, suppresses the DDR. THD was previously shown to improve therapeutic response in combination with DNA damaging agents . Furthermore, THD was shown to cause growth inhibition of ovarian cancer cells via suppression of AKT activity by an unidentified mechanism downstream of PI3K and mTOR, but which we now propose could be the result of inhibition of TLK1 and another of its targets, AKTIP, which is a direct activator of AKT.…”

“…THD was previously shown to improve therapeutic response in combination with DNA damaging agents. [11][12][13][14][15] Furthermore, THD was shown to cause growth inhibition of ovarian cancer cells via suppression of AKT activity 16 by an unidentified mechanism downstream of PI3K and mTOR, but which we now propose could be the result of inhibition of TLK1 and another of its targets, AKTIP, which is a direct activator of AKT. What is noteworthy is that the concomitant inhibition of TLK1 along with ADT (the current standard of care for advanced PCa) can result in a specific killing of Androgen Responsive PCa cells, instead of the more generalized, and thus more prone to side effects, inhibition of ATR or ATM.…”

Targeting cancer stem cells with dietary phytochemical - Repositioned drug combinations

“…Thioridazine targets CSCs. It can inhibit CSCs from a spectrum of origins: myeloid leukemia, glioblastoma, lung, liver, ovarian and breast cancers [114][115][116][117][118]. It inhibits CSC spheroid formation and induces apoptosis in vitro, and the treated cells show reduced xenograft tumor volume in mice.…”

“…In glioblastoma CSCs, it induced autophagy (seen as expression of biomarker LC3) [114]. In lung, hepatoma and breast CSCs, it induced apoptosis in association with activation of caspases, inhibition of "stemness" gene expression (Oct4, CD133), and inhibition of the mTOR pathway, respectively [115][116][117]. Synergy with conventional drug has been shown: thioridazine was co-delivered with doxorubicin in mixed polymeric micelles to target both breast CSCs and bulk cancer cells [118].…”

Chemoresistance of Lung Cancer Cells: 2D and 3D In Vitro Models for Anticancer Drug Screening

“…against LTs have been published. In vivo studies have been performed to explore and extend observed drug efficacy against LTs in a more physiological setting [87,88]. Several studies have tried combination therapy approaches in LTs setting to develop effective drug combinations to alleviate therapy resistance-related concerns and improve efficacy of existing cancer drugs [68,[89][90][91][92].…”