Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species

Kim, Ukjin; Kim, C‐Yoon; Lee, Ji Min; Ryu, Bokyeong; Kim, Jin; Shin, Choonsung; Park, Jae‐Hak

doi:10.3389/fphar.2019.01517

Cited by 20 publications

(18 citation statements)

References 35 publications

(40 reference statements)

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“…The present study has identified the SNHG17/β-catenin/TCF axis in PCa tumor cells; however, the possibility that other mechanisms may also be involved cannot be excluded. For example, Kim et al ( 34 ) reported that pimozide repressed the proliferation of PCa tumor cell lines (PC3 and DU145) via the generation of reactive oxygen species (ROS). Takeuchi et al ( 35 ) also reported that ROS was associated with the proapoptotic activity of bladder cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA SNHG17 enhances the aggressiveness of C4‑2 human prostate cancer cells in association with β‑catenin signaling

et al. 2021

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Long non-coding (lnc) RNAs have emerged as important regulators of cancer development and progression. Several lncRNAs have been reported to be associated with prostate cancer (PCa); however, the involvement of lncRNA SNHG17 in PCa remains unclear. In the present study, the mRNA expression level of SNHG17 in 58 pairs of PCa tumor samples and adjacent non-tumor tissues, as well as in PCa tumor cell lines was analyzed. The regulatory effect of SNHG17 on the oncogenic phenotypes of the C4-2 tumor cell line was also investigated. The clinicopathological analysis revealed that SNHG17 mRNA expression level was increased in the PCa tumor samples, and its high expression levels were associated with poor patient outcomes, indicating that SNHG17 may act as a biomarker for the prognosis of PCa. SNHG17 mRNA expression level was also increased in different PCa tumor cell lines. Functionally, SNHG17 increased C4-2 tumor cell growth and aggressiveness by stimulating tumor cell proliferation, survival, invasion and resistance to chemotherapy. Furthermore, SNHG17 promoted in vivo tumor growth in a xenograft mouse model. Notably, the SNHG17-induced in vitro and in vivo oncogenic effects were associated with activation of the β-catenin pathway. The results from the present study revealed that lncRNA SNHG17 could be an important regulator in the oncogenic properties of human PCa and may; therefore, represent a potential PCa therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA SNHG17 enhances the aggressiveness of C4‑2 human prostate cancer cells in association with β‑catenin signaling

et al. 2021

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“…Pimozide, an FDA-approved psychotropic drug, inactivated STAT5a and downregulated the expression of ABCB1, thus sensitizing MCF7/DOX cells to DOX in vitro and in vivo, providing a promising strategy for treating patients with chemoresistant breast cancer in the clinic. In fact, pimozide has been found to have antitumor activity mediated by suppressing STAT5 in various types of cancer (25,(42)(43)(44). In breast cancer, pimozide has also been proven to promote apoptosis by inhibiting RAN GTPase and AKT and to inhibit epithelial-mesenchymal transition and cell migration (45).…”

Section: Discussionmentioning

confidence: 99%

STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1

Chen

Cao

et al. 2021

Front. Oncol.

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Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance in vivo. Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.

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“…Mechanistically, the efficacy of both Pimozide and Fluspirilene towards intracellular Mtb was inhibited by ROS/RNS inhibitors. Of these two diphenylbutylpiperidines, only Pimozide is known to induce ROS/RNS production and to inhibit the expression of antioxidant genes, like catalase, in vitro as well as in vivo [57,78]. Interestingly, similar to the results from Cai, Zhou [57], addition of n-acetyl-cysteine (NAC), a general ROS scavenger, partly inhibited the Pimozide induced increase in ROS/RNS levels by human macrophages, and reduced bacterial survival (Figure 5B and D).…”

Section: Discussionmentioning

confidence: 99%

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy ofMycobacterium tuberculosisandSalmonella entericainfections

Heemskerk

Korbee

Esselink

et al. 2021

Preprint

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The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis (TB) treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide's and Fluspirilene's efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

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Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species

Cited by 20 publications

References 35 publications

Long non‑coding RNA SNHG17 enhances the aggressiveness of C4‑2 human prostate cancer cells in association with β‑catenin signaling

Long non‑coding RNA SNHG17 enhances the aggressiveness of C4‑2 human prostate cancer cells in association with β‑catenin signaling

STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy ofMycobacterium tuberculosisandSalmonella entericainfections

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