Repurposing the Antipsychotic Trifluoperazine as an Antimetastasis Agent

Pulkoski‐Gross, Ashleigh; Li, Jian; Zheng, Carolina; Li, Yiyi; Ouyang, Nengtai; Rigas, Basil; Zucker, Stanley; Cao, Jian

doi:10.1124/mol.114.096941

Cited by 54 publications

(41 citation statements)

References 53 publications

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“…TFP is an effective antipsychotic drug for people with schizophrenia (34), acting by blocking central dopamine receptors. In early attempts to repurpose the drug, TFP and some of its derived compounds were noted to have anticancer effects in some (35)(36)(37)(38) but not all cancer models (39). However, TFP cannot be used in clinic for treating patients with cancer, due to the numerous undesirable side effects that occur at efficient anticancer doses.…”

Section: Discussionmentioning

confidence: 99%

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Santofimia‐Castaño¹,

Xia²,

Lan³

et al. 2019

Journal of Clinical Investigation

102

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Section: Discussionmentioning

confidence: 99%

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Santofimia‐Castaño¹,

Xia²,

Lan³

et al. 2019

Journal of Clinical Investigation

102

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“…S1), such as an antihistamine drug astemizole [57, 58], an antipsychotic trifluoperazine [59], and an anti-protozoal quinacrine [60], are also approved drugs that have been reported to show anti-angiogenic and anticancer properties. Although precise mechanisms of these drugs for anti-angiogenic effects remain elusive, we believe that inhibition of cholesterol trafficking is likely the primary mechanism of action as evidenced by the cholesterol rescue effects.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Lyu

Yang

Head³

et al. 2017

Cancer Letters

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Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents.

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“…(35-38) In addition, a recent compound library screen of the NCI-60 cell line repository identified the anti-psychotic trifluoperzine (TFP)—a DRD2 antagonist—as a potential anti-metastatic cancer drug. (12) In lung cancer, TFP inhibits the ß-catenin pathway and diminishes the stem-like phenotype. (39) It also reversed gefitinib-resistance.…”

Section: Discussionmentioning

confidence: 99%

Relationship between anti-depressant use and lung cancer survival

Zingone

Brown

Bowman

et al. 2017

Cancer Treatment and Research Communications

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Objectives In recent years, the anti-cancer properties of several commonly used drugs have been explored, with drugs such as aspirin and beta-blockers associated with improved cancer outcomes. Previous preclinical work demonstrated that tricyclic anti-depressants have antitumor efficacy in lung cancer. Our goal was to examine the association between anti-depressant use and survival in lung cancer. Materials and Methods We examined the association between use of common anti-depressants and survival in 1,097 lung cancer patients from the NCI-Maryland lung cancer study. The types of anti-depressants included in the study were norepinephrine and dopamine reuptake inhibitors, serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, and tricyclic anti-depressants. Anti-depressant use was extracted from the medical history section of a detailed interviewer-administered questionnaire. Specific use in the three months before a lung cancer diagnosis was determined. Cox portioned hazards modeling was used to estimate the association between anti-depressant use with lung cancer-specific death with adjustment for potential confounding co-factors. Results Anti-depressant use was associated with extended lung cancer-specific survival. In an analysis of specific classes of anti-depressant use, NDRIs and TCAs were associated with improved survival. Importantly, the extended survival associated with anti-depressants was maintained after adjustment for the clinical indications for these drugs, suggestive of a direct effect on lung cancer biology. Conclusions Considering the manageable and largely tolerable side effects of anti-depressants, and the low cost of these drugs, these results indicate that evaluation of anti-depressants as adjunct therapeutics with chemotherapy may have a translational effect for lung cancer patients.

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Repurposing the Antipsychotic Trifluoperazine as an Antimetastasis Agent

Cited by 54 publications

References 53 publications

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Relationship between anti-depressant use and lung cancer survival

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