Thioridazine hydrochloride: an antipsychotic agent that inhibits tumor growth and lung metastasis in triple-negative breast cancer via inducing G0/G1 arrest and apoptosis

Song, Yanlin; Li, Lü; Chen, Jiao; Chen, Hongli; Cui, Bomiao; Feng, Yun; Zhang, Ping; Zhang, Qiangsheng; Xia, Yong; Luo, Min

doi:10.1080/15384101.2020.1850969

Cited by 10 publications

(14 citation statements)

References 36 publications

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“…Several previous studies have identified possible pathways through which antipsychotics promote breast cancer ( 14 , 15 ). In contrast, other studies have found that some antipsychotic drugs or antipsychotics that induced HPRL can prevent the growth or metastasis of breast tumor cells ( 16 , 17 ). However, the conclusions of different clinical trials also remain controversial.…”

Section: Introductionmentioning

confidence: 79%

Antipsychotic exposure is an independent risk factor for breast cancer: A systematic review of epidemiological evidence

et al. 2022

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BackgroundThe effect of antipsychotics on breast cancer remains controversial.Materials and methodsEmbase, Scopus, PubMed, Web of Science, Cochrane Library, and Hebei Medical University Library were used for the literature search. Observational studies with original data for the effects of antipsychotics on breast cancer were used. Studies of bed quality, those with inadequate sample size, incomplete follow-up works, or studies that did not meet the criteria were excluded. Meta-analysis was performed using R version 4.1.2. The odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the proportion of breast cancer in different groups. To detect possible sources of heterogeneity, subgroup and meta-regression analyses were employed.ResultsPooled data from 11 relevant studies with 1,499,001 participants suggested that individuals exposed to antipsychotics were more likely to suffer from breast cancer than those who were not exposed (OR, 1.23; 95% CI, 1.04–1.47). No significant difference in breast cancer prevalence between the atypical and typical antipsychotic groups was found (OR, 1.23; 95% CI, 0.93–1.63). Prolactin (PRL)-increasing and PRL-sparing antipsychotics posed a similar risk of breast cancer (OR, 1.13; 95% CI, approximately 0.97–1.31). Furthermore, the use of antipsychotics is attributed to increased mortality in patients with breast cancer (OR, 1.54; 95% CI, 1.29–1.82). Those exposed to antipsychotics at the maximum dose were more likely to suffer from breast cancer than those exposed to the minimum dose.ConclusionsAntipsychotic exposure is an independent risk factor for breast cancer. No significant difference in the risk of breast cancer between typical and atypical antipsychotics was noted. Those exposed to antipsychotics at higher doses are more likely to suffer from breast cancer. Moreover, the use of antipsychotics is attributed to increased mortality in patients with breast cancer. PRL-increasing and PRL-sparing antipsychotics pose a similar risk of breast cancer.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022307624.

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Section: Introductionmentioning

confidence: 79%

Antipsychotic exposure is an independent risk factor for breast cancer: A systematic review of epidemiological evidence

et al. 2022

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“…While a G1/G0 cell cycle arrest was described for trifluoperazine ( 31 – 34 ), thioridazine ( 20 , 35 ) and FLU ( 29 ), only CPZ is reported to induce a G2/M arrest, and more specifically to induce a mitotic catastrophe ( 36 – 38 ). We first confirmed that CPZ-induced toxicity in A375 cells correlated with a cell cycle arrest in G2/M ( Figures 3A, B ).…”

Section: Resultsmentioning

confidence: 99%

The anti-cancer efficacy of a novel phenothiazine derivative is independent of dopamine and serotonin receptor inhibition

Vanneste,

Venzke,

Guin

et al. 2023

Front. Oncol.

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IntroductionAn attractive, yet unrealized, goal in cancer therapy is repurposing psychiatric drugs that can readily penetrate the blood-brain barrier for the treatment of primary brain tumors and brain metastases. Phenothiazines (PTZs) have demonstrated anti-cancer properties through a variety of mechanisms. However, it remains unclear whether these effects are entirely separate from their activity as dopamine and serotonin receptor (DR/5-HTR) antagonists.MethodsIn this study, we evaluated the anti-cancer efficacy of a novel PTZ analog, CWHM-974, that was shown to be 100-1000-fold less potent against DR/5-HTR than its analog fluphenazine (FLU).ResultsCWHM-974 was more potent than FLU against a panel of cancer cell lines, thus clearly demonstrating that its anti-cancer effects were independent of DR/5-HTR signaling. Our results further suggested that calmodulin (CaM) binding may be necessary, but not sufficient, to explain the anti-cancer effects of CWHM-974. While both FLU and CWHM-974 induced apoptosis, they induced distinct effects on the cell cycle (G0/G1 and mitotic arrest respectively) suggesting that they may have differential effects on CaM-binding proteins involved in cell cycle regulation. DiscussionAltogether, our findings indicated that the anti-cancer efficacy of the CWHM-974 is separable from DR/5-HTR antagonism. Thus, reducing the toxicity associated with phenothiazines related to DR/5-HTR antagonism may improve the potential to repurpose this class of drugs to treat brain tumors and/or brain metastasis

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“…Although it has been reported that more than 95% of breast cancer cells overexpress prolactin receptors which are closely related to tumorigenesis and cell proliferation [ 22 , 23 ], it is still obscure how the increased prolactin by antipsychotics use is associated with the occurrence of breast cancer. Previous experimental studies have reported inconsistent findings regarding the effect of antipsychotics on the proliferation of breast cancer cells, where some antipsychotic drugs suppress the growth and proliferation of breast cancer cells [ 7 , 24 - 26 ], while hyperprolactinemia-inducing antipsy-chotics promote breast cancer by activating JAK-STAT5 in precancerous lesions [ 6 ]. The current study showed that antipsychotics having a low risk of hyperprolactinemia were also associated with a higher risk of breast cancer, which suggests that the effect of hyperprolactinemia is not sufficient to comprehensively elucidate the relationship between antipsychotics use and the development of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Risk of Breast Cancer in Association with the Use of Second-generation Antipsychotics

Joo

Lee

et al. 2022

Clin Psychopharmacol Neurosci

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Objective: Previous studies regarding the relationship between the risk of breast cancer (BC) and antipsychotics use have reported inconsistent findings. Insufficient sample size and/or observation period may have hindered revealing the risk of BC associated with antipsychotics use. We aimed to investigate whether the use of second-generation antipsychotics (SGA) is associated with increased risk of BC. Methods: We used the Health Insurance Review Agency database in South Korea between 2008 and 2018. The index date was determined as the date of the first antipsychotic prescription. We selected women prescribed SGAs for more than 30 days within a year from the index date and age-matched controls, yielding 498,970 cases and 997,940 controls. The Cox proportional hazards regression model was used for estimating the risk. Results: The incidence rates of BC were 109.74 and 101.51 per 100,000 person-years in the case and control groups, respectively. There was an increased risk of BC in the case group (hazard ratio [HR] = 1.08, 95% confidence interval [CI] 1.04−1.13). There was a higher risk of BC in subjects prescribed with ≥ 10,000 mg of olanzapine equivalent dose (HR = 1.29, 95% CI 1.14−1.46) than those with ＜ 10,000 mg (HR = 1.05, 95% CI 1.00−1.11). The increased risk of BC in the case group became significant after six years of the observation period (≥ 6 years: HR = 1.24, 95% CI 1.14−1.35, 3 to ＜ 6 years: HR = 1.06, 95% CI 0.97−1.15, ＜ 3 years: HR = 1.02, 95% CI 0.95−1.09). Conclusion: This study indicated that the use of SGAs is associated with increased risk of BC in a long-term relationship with a dose-response pattern.

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Thioridazine hydrochloride: an antipsychotic agent that inhibits tumor growth and lung metastasis in triple-negative breast cancer via inducing G0/G1 arrest and apoptosis

Cited by 10 publications

References 36 publications

Antipsychotic exposure is an independent risk factor for breast cancer: A systematic review of epidemiological evidence

Antipsychotic exposure is an independent risk factor for breast cancer: A systematic review of epidemiological evidence

The anti-cancer efficacy of a novel phenothiazine derivative is independent of dopamine and serotonin receptor inhibition

Risk of Breast Cancer in Association with the Use of Second-generation Antipsychotics

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