Treatment of cancer with antipsychotic medications: Pushing the boundaries of schizophrenia and cancer

Brown, James S.

doi:10.1016/j.neubiorev.2022.104809

Cited by 17 publications

(20 citation statements)

References 383 publications

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“…However, a meta-analysis involving 12 studies and 496,265 patients found no significant increase in the incidence rate ratio when comparing the incidence of lung cancer between individuals with schizophrenia (SCZ) and the general population. [ 46 ] It is hypothesized that this lack of significance may be partially attributed to the protective effect of antipsychotic medication, [ 47 , 48 ] which counteracts the cancer-promoting effect of schizophrenia. Moreover, Individuals with schizophrenia often experience healthcare disparities owing to stigma, physician bias, and poor integration of mental health and medical care.…”

Section: Discussionmentioning

confidence: 99%

The causal relationship between severe mental illness and risk of lung carcinoma

Chen,

Wang,

Shen

2024

Medicine

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Observational studies have suggested a link between severe mental illness (SMI) and risk of lung carcinoma (LC); however, causality has not been established. In this study, we conducted a two-sample, two-step Mendelian randomization (MR) investigation to uncover the etiological influence of SMI on LC risk and quantify the mediating effects of known modifiable risk factors. We obtained summary-level datasets for schizophrenia, major depressive disorder (MDD), and bipolar disorder (BD) from the Psychiatric Genomics Consortium (PGC). Data on single nucleotide polymorphisms (SNPs) associated with lung carcinoma (LC) were sourced from a recent large meta-analysis by McKay et al. We employed two-sample MR and two-step MR utilizing the inverse variance weighted method for causal estimation. Sensitivity tests were conducted to validate causal relationships. In two-sample MR, we identified schizophrenia as a risk factor for LC (OR = 1.06, 95% CI 1.02–1.11, P = 3.48E-03), while MDD (OR = 1.18, 95% CI 0.98–1.42, P = .07) and BD (OR = 1.07, 95% CI 0.99–1.15, P = .09) showed no significant association with LC. In the two-step MR, smoking accounted for 24.66% of the schizophrenia-LC risk association, and alcohol consumption explained 7.59% of the effect. Schizophrenia is a risk factor for lung carcinoma, and smoking and alcohol consumption are the mediating factors in this causal relationship. LC screening should be emphasized in individuals with schizophrenia, particularly in those who smoke and consume alcohol regularly.

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Section: Discussionmentioning

confidence: 99%

The causal relationship between severe mental illness and risk of lung carcinoma

Chen,

Wang,

Shen

2024

Medicine

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“…The phenothiazines (PTZs), discovered by Erlich in the 1920’s and developed as anti-psychotic agents in the 1950’s, inhibit dopamine receptors (DRs), particularly the D2-type, as well as serotonin receptors (5-HTRs) ( 9 ). Motivated by epidemiologic studies indicating that the use of PTZs may be associated with reduced cancer risk, numerous efforts have investigated the potential anti-cancer properties of these drugs over the past couple of decades ( 10 , 11 ). Most of these studies have focused on chlorpromazine (CPZ), thioridazine and trifluoperazine ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

“…Motivated by epidemiologic studies indicating that the use of PTZs may be associated with reduced cancer risk, numerous efforts have investigated the potential anti-cancer properties of these drugs over the past couple of decades ( 10 , 11 ). Most of these studies have focused on chlorpromazine (CPZ), thioridazine and trifluoperazine ( 10 , 11 ). However, to date, only thioridazine completed a phase 1 clinical trial (NCT02096289) for relapsed or refractory acute myeloid leukemia with preliminary results suggesting that DRD2 represents a potential therapeutic target for this disease ( 12 ).…”

Section: Introductionmentioning

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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“…Orally administered bipolar drugs have been shown to target antagonists for dopamine receptors on brain cell membranes [14,15]. Bipolar drugs have shown anticancer activity in various models for a long time [16][17][18][19][20], with clinical trials being held in cancer patients. Bipolar drugs for glioma treatment are beneficial, and their ability to penetrate the bloodbrain barrier at low doses has been tested.…”

Section: Introductionmentioning

confidence: 99%

“…These drugs can be used as potential candidates for first-line combination treatments and repositioned at low doses. The drugs include aripiprazole, fluphenazine, thioridazine, trifluopherazine, pimozide, quetiapine, loxapine, and iloperidone [14][15][16][17][18][19][20] (Table 1). Combination therapy with low-dose bipolar drugs is the focus of the discussion in the present review.…”

Section: Introductionmentioning

confidence: 99%

First-Line Combination Treatment with Low-Dose Bipolar Drugs for ABCB1-Overexpressing Drug-Resistant Cancer Populations

Yoon

Kim

2023

IJMS

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Tumors include a heterogeneous population, of which a small proportion includes drug-resistant cancer (stem) cells. In drug-sensitive cancer populations, first-line chemotherapy reduces tumor volume via apoptosis. However, it stimulates drug-resistant cancer populations and finally results in tumor recurrence. Recurrent tumors are unresponsive to chemotherapeutic drugs and are primarily drug-resistant cancers. Therefore, increased apoptosis in drug-resistant cancer cells in heterogeneous populations is important in first-line chemotherapeutic treatments. The overexpression of ABCB1 (or P-gp) on cell membranes is an important characteristic of drug-resistant cancer cells; therefore, first-line combination treatments with P-gp inhibitors could delay tumor recurrence. Low doses of bipolar drugs showed P-gp inhibitory activity, and their use as a combined therapy sensitized drug-resistant cancer cells. FDA-approved bipolar drugs have been used in clinics for a long period of time, and their toxicities are well reported. They can be easily applied as first-line combination treatments for targeting resistant cancer populations. To apply bipolar drugs faster in first-line combination treatments, knowledge of their complete information is crucial. This review discusses the use of low-dose bipolar drugs in sensitizing ABCB1-overexpressing, drug-resistant cancers. We believe that this review will contribute to facilitating first-line combination treatments with low-dose bipolar drugs for targeting drug-resistant cancer populations. In addition, our findings may aid further investigations into targeting drug-resistant cancer populations with low-dose bipolar drugs.

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Treatment of cancer with antipsychotic medications: Pushing the boundaries of schizophrenia and cancer

Cited by 17 publications

References 383 publications

The causal relationship between severe mental illness and risk of lung carcinoma

The causal relationship between severe mental illness and risk of lung carcinoma

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

First-Line Combination Treatment with Low-Dose Bipolar Drugs for ABCB1-Overexpressing Drug-Resistant Cancer Populations

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