Abstract
Thioridazine has been known as an antipsychotic agent, but it also has anticancer activity. However, the effect of thioridazine on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitization has not yet been studied. Here, we investigated the ability of thioridazine to sensitize TRAIL-mediated apoptosis. Combined treatment with thioridazine and TRAIL markedly induced apoptosis in various human carcinoma cells, including renal carcinoma (Caki, ACHN, and A498), breast carcinoma (MDA-MB231), and glioma (U251MG) cells, but not in normal mouse kidney cells (TMCK-1) and human normal mesangial cells. We found that thioridazine downregulated c-FLIP(L) and Mcl-1 expression at the post-translational level via an increase in proteasome activity. The overexpression of c-FLIP(L) and Mcl-1 overcame thioridazine plus TRAIL-induced apoptosis. We further observed that thioridazine inhibited the Akt signaling pathway. In contrast, although other phosphatidylinositol-3-kinase/Akt inhibitors (LY294002 and wortmannin) sensitized TRAIL-mediated apoptosis, c-FLIP(L) and Mcl-1 expressions were not altered. Furthermore, thioridazine increased the production of reactive oxygen species (ROS) in Caki cells, and ROS scavengers (N-acetylcysteine, glutathione ethyl ester, and trolox) inhibited thioridazine plus TRAIL-induced apoptosis, as well as Akt inhibition and the downregulation of c-FLIP(L) and Mcl-1. Collectively, our study demonstrates that thioridazine enhances TRAIL-mediated apoptosis via the ROS-mediated inhibition of Akt signaling and the downregulation of c-FLIP(L) and Mcl-1 at the post-translational level.
Highlights
Phenothiazine) is a first-generation antipsychotic drug that has been used to treat psychotic disorders, such as psychosis and schizophrenia.[1,2] Thioridazine has antimicrobial activity and is used as a treatment against drug-resistant organisms, such as Mycobacterium tuberculosis.[3,4] In addition, thioridazine has anticancer effects, including antiproliferative and antisurvival effects
To identify the mechanisms underlying sensitization to Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by thioridazine, we examined the expression levels of apoptosis-related proteins, including the Bcl-2 family, IAP family, constituents of death-inducing signaling complex (DISC) (FADD and cellular FLICE-inhibitory protein (c-FLIP(L)), and death receptors (DRs) in thioridazine-treated Caki cells
We demonstrated the mechanism that underlies the sensitization to TRAIL-mediated apoptosis due to thioridazine
Summary
Phenothiazine) is a first-generation antipsychotic drug that has been used to treat psychotic disorders, such as psychosis and schizophrenia.[1,2] Thioridazine has antimicrobial activity and is used as a treatment against drug-resistant organisms, such as Mycobacterium tuberculosis.[3,4] In addition, thioridazine has anticancer effects, including antiproliferative and antisurvival effects. Previous studies have shown that cancer cells highly express DRs, whereas normal cells highly express the decoy receptors.[13] the level of cellular FLICE-inhibiting protein (c-FLIP(L)), which inhibits caspase-8 recruitment to DISC, is higher in normal cells than in tumor cells.[14] TRAIL had been known as a promising anticancer drug.[15] many cancer cells represent resistance to TRAIL-mediated apoptosis via multiple mechanisms. The downregulation of DRs and/or upregulation of antiapoptotic proteins (c-FLIP(L), the Bcl-2 family proteins (Bcl-2, Bcl-xL, and Mcl-1) and the inhibitor of apoptosis proteins (IAPs)) have been demonstrated to be associated with TRAIL resistance.[16,17,18,19,20] Previous studies have shown that TRAILresistant cancer cells can be sensitized by combination treatment. Combination treatment with TRAIL and thioridazine could facilitate the development of an effective strategy for cancer treatment
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