Antipsychotic dopamine receptor antagonists, cancer, and cancer stem cells

Roney, Md Saiful Islam; Park, Song‐Kyu

doi:10.1007/s12272-018-1017-3

Cited by 45 publications

(43 citation statements)

References 270 publications

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“…Interestingly, previous studies have already shown antiproliferative and migrastatic effects of pimozide in pancreatic cancer cells with high expression levels of DRD2, MDA‐MB‐231 breast cancer cells, and A549 lung cancer cells . Consequently, many antipsychotic dopamine receptor antagonists have recently been tested in a variety of cancer cells, and these drugs inhibit the growth of cancer cells through the modulation of different targets, such as DRD2, STAT, and AKT .…”

Section: Discussionmentioning

confidence: 99%

Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex

et al. 2019

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ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule. To identify ARPC2 inhibitors, we generated an ARPC2 knockout DLD‐1 human colon cancer cell line using the clustered regularly interspaced short palindromic repeats/CRISPR‐associated protein 9 (CRISPR/Cas9) system and explored gene signature‐based strategies, such as a connectivity map (CMap) using the gene expression profiling data of ARPC2 knockout and knockdown cells. From the CMap‐based drug discovery strategy, we identified pimozide (a clinically used antipsychotic drug) as a migrastatic drug and ARPC2 inhibitor. Pimozide inhibited the migration and invasion of various cancer cells. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2. Pimozide increased the lag phase of Arp2/3 complex‐dependent actin polymerization and inhibited the vinculin‐mediated recruitment of ARPC2 to focal adhesions in cancer cells. To validate the likely binding of pimozide to ARPC2, mutant cells, including ARPC2F225A, ARPC2F247A and ARPC2Y250F cells, were prepared using ARPC2 knockout cells prepared by gene‐editing technology. Pimozide strongly inhibited the migration of mutant cells because the mutated ARPC2 likely has a larger binding pocket than the wild‐type ARPC2. Therefore, pimozide is a potential ARPC2 inhibitor, and ARPC2 is a new molecular target. Taken together, the results of the present study provide new insights into the molecular mechanism and target that are responsible for the antitumor and antimetastatic activity of pimozide.

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Section: Discussionmentioning

confidence: 99%

Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex

et al. 2019

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Section: Discussionmentioning

confidence: 99%

“…There are several reports indicating elevated DRD2 expression in cancer cells compared to normal cells in several cancer types, and DRD2 overexpression correlates with an advanced stage and stemness of cancer and a poor prognosis of patients 7 , 9 , 24 . Moreover, antagonizing DRD2 signaling either by DRD2 antagonists, such as thioridazine and trifluoperazine, or genetic depletion show the proapoptotic, antimetastatic, antiangiogenic, and anticancer stem cell properties in several tumor types 7 , 10 , 25 . At present, DRD2 genetic variants have been reported to affect the expression and function of DRD2 and to be correlated with the susceptibility and clinicopathologic development of cancers such as colon and lung cancers, and pituitary adenomas 17 , 18 , 22 , 26 .…”

Section: Discussionmentioning

confidence: 99%

“…DRs are divided into the D1-like class (DRD1 and DRD5) and D2-like class (DRD2, DRD3, and DRD4). These receptors work antagonistically to modulate the synthesis of cyclic adenosine monophosphate (cAMP) and activity of protein kinase A (PKA) 7 . Dysregulated dopamine secretion or inactivation of DRs was reported to correlate with various neurological diseases such as schizophrenia and Parkinson's disease 8 .…”

Section: Introductionmentioning

confidence: 99%

“…Dysregulated dopamine secretion or inactivation of DRs was reported to correlate with various neurological diseases such as schizophrenia and Parkinson's disease 8 . In addition to the traditional function of DRs in neurological diseases, among DRs, DRD2 especially was reported to be overexpressed in different cancer types, including cervical, lung, pituitary, colon, and gastric cancers and to be correlated with poor prognoses of these cancers 7 , 9 . Moreover, blocking DRD2 was shown to suppress proliferation and induce apoptosis of both cancer cells and cancer stem cells 7 , 10 .…”

Section: Introductionmentioning

confidence: 99%

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Dopamine receptor D2 genetic variations is associated with the risk and clinicopathological variables of urothelial cell carcinoma in a Taiwanese population

Tung¹,

Wen²,

Wang³

et al. 2018

Int. J. Med. Sci.

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Dopamine receptor D2 (DRD2) is overexpressed in several kinds of cancers and was correlated with the prognosis of these cancers. Polymorphisms within the DRD2 gene were shown to be associated with lung and colon cancers. The purpose of this study was to explore effects of DRD2 gene polymorphisms on the susceptibility to and clinicopathological characteristics of urothelial cell carcinoma (UCC). In total, 369 patients diagnosed with UCC and 738 healthy controls were enrolled to analyze DRD2 genotypes at four loci (rs1799732, -141C>del; rs1079597, TaqIB; rs6277, 957C>T; and rs1800497, TaqIA) using a TaqMan-based real-time polymerase chain reaction (PCR). We found a significantly lower risk for UCC in individuals with the DRD2 rs6277 CT genotype compared to those with the wild-type CC genotype (adjusted odds ratio (AOR)=0.405, 95% confidence interval (CI): 0.196~0.837, p=0.015). In 124 younger patients (aged < 65 years) of the recruited UCC cohort, patients who carried at least one T allele of DRD2 rs1800497 were at higher risk (AOR=2.270, 95% CI: 1.060~4.860, p=0.033) of developing an invasive stage (pT2~pT4). In 128 female patients of the recruited UCC cohort, patients who carried at least one deletion allele of DRD2 rs1799732 showed a higher incidence of having an invasive stage (AOR=2.585, 95% CI: 1.066~6.264, p=0.032) and a large tumor (AOR=2.778, 95% CI: 1.146~6.735, p=0.021). Further analyses of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed correlations of the expression of DRD2 with an invasive tumor, tumor metastasis, and the lower survival rate in patients with UCC. Our findings suggest that DRD2 levels might affect the progression of UCC, and the polymorphisms rs6277, rs1800497, and rs1799732 of DRD2 are probably associated with the susceptibility and clinicopathologic development of UCC in a Taiwanese population.

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Antipsychotic use is inversely associated with gastric cancer risk: A nationwide population‐based nested case‐control study

et al. 2019

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Objective The association between antipsychotic use and gastric cancer risk remains unclear. Therefore, this study aimed to determine the association between antipsychotic exposure and the incidence of gastric cancer. Methods Using a nested case‐control design, a total of 34 470 gastric cancer patients and 163 430 nongastric cancer controls were identified from Taiwan's National Health Insurance Research Database between 1 January 1997 and 31 December 2013. We analyzed the data using a conditional logistic regression model to adjust for possible confounding variables. Results Antipsychotic use was independently inversely associated with gastric cancer risk after controlling for potential confounding factors including income, urbanization, medications, physical and medical illness, aspirin use, nonsteroidal anti‐inflammatory drug use and triple therapy. In addition, dose‐dependent trends against gastric cancer risk were also shown with individual antipsychotic compounds including thioridazine, haloperidol, sulpiride, clozapine, olanzapine, quetiapine, amisulpride, and risperidone. A sensitivity analysis showed that second‐generation antipsychotics had significant dose‐dependent effects in reducing the risk of gastric cancer risk in patients with and without peptic ulcer disease. Conclusions Antipsychotic use was inversely associated with gastric cancer risk, and dose‐dependent effects against gastric cancer were also seen with several individual antipsychotic compounds.

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Antipsychotic dopamine receptor antagonists, cancer, and cancer stem cells

Cited by 45 publications

References 270 publications

Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex

Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex

Dopamine receptor D2 genetic variations is associated with the risk and clinicopathological variables of urothelial cell carcinoma in a Taiwanese population

Antipsychotic use is inversely associated with gastric cancer risk: A nationwide population‐based nested case‐control study

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