Repurposing antipsychotics of the diphenylbutylpiperidine class for cancer therapy

Shaw, Vikram; Srivastava, Suyash; Srivastava, Sanjay

doi:10.1016/j.semcancer.2019.10.007

Cited by 61 publications

(41 citation statements)

References 64 publications

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“…Some compounds investigated in this study, including the antipsychotics diphenylbutylpiperidines fluspirilene, penfluridol, and pimozide and antidepressants such as fluoxetine have been previously reported as autophagy inducers in neurons and in different cancer cell types such as BC and GB by affecting a variety of targets (31,(71)(72)(73). Our study shows that the cytotoxic activity of most of these compounds is essentially based on their common cationic amphiphilic properties and their capacity to perturb acidic intracellular compartments.…”

Section: Discussionmentioning

confidence: 74%

“…Epidemiological studies have repeatedly reported that individuals who are receiving long term drug treatment with antipsychotics (24,25), anti-depressant (26)(27)(28) or anti-allergic drugs (29) have a lower cancer incidence than the general population, suggesting that these medications might have a direct effect on neoplastic cells. Pre-clinical studies confirmed the direct anti-tumoral activity of these compounds in a wide range of malignancies (30)(31)(32)(33)(34). However, despite the large body of experimental evidence, the mechanisms of actions of these compounds in cancer cells remain poorly defined.…”

Section: Introductionmentioning

confidence: 99%

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Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

et al. 2020

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Background and Purpose: Drug repositioning is a promising strategy for discovering new therapeutic strategies for cancer therapy. We investigated psychotropic drugs for their antitumor activity because of several epidemiological studies reporting lower cancer incidence in individuals receiving long term drug treatment. Experimental Approach: We investigated 27 psychotropic drugs for their cytotoxic activity in colorectal carcinoma, glioblastoma and breast cancer cell lines. Consistent with the cationic amphiphilic structure of the most cytotoxic compounds, we investigated their effect on mitochondrial and lysosomal compartments. Results: Penfluridol, ebastine, pimozide and fluoxetine, fluspirilene and nefazodone showed significant cytotoxicity, in the low micromolar range, in all cell lines tested. In MCF7 cells these drugs caused mitochondrial membrane depolarization, increased the acidic vesicular compartments and induced phospholipidosis. Both penfluridol and spiperone induced AMPK activation and autophagy. Neither caspase nor autophagy inhibitors rescued cells from death induced by ebastine, fluoxetine, fluspirilene and nefazodone. Treatment with 3-methyladenine partially rescued cell death induced by pimozide and spiperone, whereas enhanced the cytotoxic activity of penfluridol. Conversely, inhibition of lysosomal cathepsins significantly reduced cell death induced by ebastin, penfluridol, pimozide, spiperone and mildly in fluoxetine treated cells. Lastly, Spiperone cytotoxicity was restricted to colorectal cancer and breast cancer and caused apoptotic cell death in MCF7 cells. Conclusions: The cytotoxicity of psychotropic drugs with cationic amphiphilic structures relied on simultaneous mitochondrial and lysosomal disruption and induction of cell death that not necessarily requires apoptosis. Since dual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for cancer, particularly those in which the apoptotic machinery is defective, these data further support their clinical development for cancer therapy.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

et al. 2020

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“…Emerging evidence has suggested that some FDA-approved antipsychotic drugs such as penfluridol, flusirilene and pimozide (typically used in the treatment of schizophrenia) may be suitable agents to repurpose in cancer treatment. These antipsychotic compounds are potent dopamine d2 and calcium channel inhibitors that are part of the diphenylbutylpiperidine class of drugs [ 108 ].…”

Section: Ion Channel Inhibitors As Therapeutic Targetsmentioning

confidence: 99%

“…Pimozide treatment of rat glioma and patient derived GBM cell lines resulted in cell cycle arrest, anti-proliferative effects and apoptosis [ 134 ]. Furthermore, pimozide may have a radio-sensitising effect, as observed in GBM mouse models, those treated with both irradiation and pimozide lived twice as long than those treated with just irradiation alone [ 108 ]. Apoptotic volume decrease is a result of fluctuations in the levels of intracellular ions, namely the loss of intracellularly K+ and is a result of decrease in ionic strength.…”

Section: Ion Channel Inhibitors As Therapeutic Targetsmentioning

confidence: 99%

Ion Channels as Therapeutic Targets in High Grade Gliomas

Griffin

Khan

Basu

et al. 2020

Cancers

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Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14–15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.

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“… 5 Antipsychotic drugs such as pimozide, penfluridol, fluspirilene, haloperidol, olanzapine, chlorpromazine, and reserpine have been demonstrated to exert antineoplastic effects in various cancer models. 6 , 7 , 8 , 9 , 10 , 11 In this study, we have repurposed pimavanserin tartrate (PVT) as a novel therapeutic option for pancreatic cancer. PVT was approved by the US Food and Drug Administration (FDA) in 2016 for the treatment of Parkinson disease psychosis (PDP).…”

Section: Introductionmentioning

confidence: 99%

Repurposing Pimavanserin, an Anti-Parkinson Drug for Pancreatic Cancer Therapy

Ramachandran

Srivastava

2020

Molecular Therapy - Oncolytics

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Despite major advances in cancer treatment, pancreatic cancer is still incurable and the treatment outcomes are limited. The aggressive and therapy-resistant nature of pancreatic cancer warrants the need for novel treatment options for pancreatic cancer management. Drug repurposing is emerging as an effectual strategy in the treatment of various diseases, including cancer. In the present study, we evaluated the anticancer effects of pimavanserin tartrate (PVT), an antipsychotic drug used for the treatment of Parkinson disease psychosis. PVT significantly suppressed the proliferation and induced apoptosis in various pancreatic cancer cells and gemcitabine-resistant cells with minimal effects on normal pancreatic epithelial cells and lung fibroblasts. Growth-suppressive and apoptotic effects of PVT were mediated by the inhibition of the Akt/Gli1 signaling axis. The oral administration of PVT suppressed subcutaneous and orthotopic pancreatic tumor xenografts by 51%–77%. The chronic administration of PVT did not demonstrate any general signs of toxicity or change in behavioral activity of mice. Our results indicate that pancreatic tumor growth suppression by PVT was orchestrated by the inhibition of Akt/Gli1 signaling. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for the treatment of patients with pancreatic cancer.

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Repurposing antipsychotics of the diphenylbutylpiperidine class for cancer therapy

Cited by 61 publications

References 64 publications

Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

Ion Channels as Therapeutic Targets in High Grade Gliomas

Repurposing Pimavanserin, an Anti-Parkinson Drug for Pancreatic Cancer Therapy

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