Antipsychotic Drug Applications in Cancer Treatment

Antipsychotic agents, originally designed for neuropsychiatric disorders, have been repurposed to target diverse mechanisms in cancer biology. Many compounds within the phenothiazine and butyrophenone families modulate key signalling pathways, trigger programmed cell death and interfere with multidrug resistance. Preclinical studies report that prolonged exposure to some antipsychotics reduces tumour incidence, particularly in lung cancer, while analogues of chlorpromazine and thioridazine exhibit proapoptotic and antiproliferative activity across a range of cancer cell lines. Mechanistically, these drugs act on the PI3K/Akt/mTOR axis, promote autophagy and cell cycle arrest, generate reactive oxygen species and inhibit efflux pumps responsible for chemotherapy resistance. Their ability to penetrate the blood–brain barrier also positions them as candidates for treating metastases in the central nervous system. Structure–activity studies continue to refine anticancer potency and selectivity, underscoring the global significance of antipsychotic repurposing in oncology.

Research from Nature Portfolio

Longitudinal data from a large adult cohort reveal that patients receiving more than one year of flupentixol have a significantly lower incidence of lung cancer compared to shorter exposure periods, indicating a potential chemopreventive effect. In models of paclitaxel-resistant metastatic breast cancer, penfluridol has been shown to downregulate HER2 and β-catenin signalling, restoring tumour chemosensitivity and reducing growth in orthotopic mouse models. Foundations in phenothiazine chemistry have led to novel trifluoperazine derivatives with markedly enhanced apoptosis-inducing activity in oral cancer cells, acting through modulation of Akt, p38 and ERK pathways, induction of autophagy and reactive oxygen species production, and demonstrating tumour suppression in xenograft experiments.

Antipsychotic Drug Applications in Cancer Treatment publication trend

The graph below shows the total number of articles in antipsychotic drug applications in cancer treatment across all publications each year (not limited to Nature Index journals).

Technical terms

Phenothiazine: A tricyclic chemical scaffold first used in antipsychotic medications, now exploited for anticancer derivatives.

Apoptosis: Programmed cell death involving caspase activation and DNA fragmentation, crucial for eliminating malignant cells.

Autophagy: A lysosome-mediated degradation process that recycles cellular components and may be harnessed to kill cancer cells.

Efflux pump: Membrane transporter proteins that export chemotherapeutic agents from cells, contributing to drug resistance.

PI3K/Akt/mTOR pathway: A central signalling cascade controlling cell growth and survival, often dysregulated in cancer and targeted by repurposed drugs.

Cell cycle arrest: The halting of cell cycle progression at defined checkpoints, preventing cancer cell proliferation.

Reactive oxygen species: Chemically reactive oxygen derivatives that induce oxidative stress and can trigger cancer cell death.

References

1. Association between cumulative exposure periods of flupentixol or any antipsychotics and risk of lung cancer. Communications Medicine (2023).
2. Penfluridol overcomes paclitaxel resistance in metastatic breast cancer. Scientific Reports (2019).
3. Novel Tetracyclic Azaphenothiazines with the Quinoline Ring as New Anticancer and Antibacterial Derivatives of Chlorpromazine. International Journal of Molecular Sciences (2024).
4. Repurposing Antidepressants and Phenothiazine Antipsychotics as Efflux Pump Inhibitors in Cancer and Infectious Diseases. Antibiotics (2023).
5. Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis (2012).
6. Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents–A drug repurposing strategy. Scientific Reports (2016).