Progress in Genetic Polymorphisms Related to Lipid Disturbances Induced by Atypical Antipsychotic Drugs

Li, Nana; Cao, Ting; Wu, Xiangxin; Tang, Mimi; Xiang, Da‐Xiong; Cai, Hualin

doi:10.3389/fphar.2019.01669

Cited by 16 publications

(15 citation statements)

References 152 publications

(144 reference statements)

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“…Targeting cancer metabolism seems to hold great promise to uncover novel targets for treatment, particularly in an obesity-driven cancer such as EC. Long-term antagonism of DRD2 with antipsychotic drugs significantly increases metabolic side effects including weight gain and disturbed lipid metabolism in patients with schizophrenia [ 41 ]. Recent studies have found that DRD2 signaling functionally alters glucose and lipid metabolisms in glioblastoma cells, and the effect of ONC201 on oxidative phosphorylation and glycolytic activity was dependent on genetic background of tumor cells [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Pierce

Fang

Yin

et al. 2021

J Exp Clin Cancer Res

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Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Methods Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. Results Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. Conclusion ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

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Section: Discussionmentioning

confidence: 99%

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Pierce

Fang

Yin

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Targeting cancer metabolism seems to hold great promise to uncover novel targets for treatment, particularly in an obesity-driven cancer such as EC. Long-term antagonism of DRD2 with antipsychotic drugs signi cantly increases metabolic side effects including weight gain and disturbed lipid metabolism in patients with schizophrenia (41). Recent studies have found that DRD2 signaling functionally alters glucose and lipid metabolisms in glioblastoma cells, and the effect of ONC201 on oxidative phosphorylation and glycolytic activity was dependent on genetic background of tumor cells (42,43).…”

Section: Discussionmentioning

confidence: 99%

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Pierce

Fang

Yin

et al. 2020

Preprint

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BackgroundONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer.MethodsCell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometriod and serous EC specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. ResultsIncreasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes.. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. ConclusionONC201 has anti-proliferative and anti-tumorigenic effects in endometrial cancer cells and mouse model, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

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“…For a comprehensive review of the candidate gene studies associated with AIWG and metabolic effects of APs see Li et al (217).…”

Section: Genetic Predispositionmentioning

confidence: 99%

The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children

Libowitz

Nurmi

2021

Front. Psychiatry

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Antipsychotic medications are critical to child and adolescent psychiatry, from the stabilization of psychotic disorders like schizophrenia, bipolar disorder, and psychotic depression to behavioral treatment of autism spectrum disorder, tic disorders, and pediatric aggression. While effective, these medications carry serious risk of adverse events—most commonly, weight gain and cardiometabolic abnormalities. Negative metabolic consequences affect up to 60% of patients and present a major obstacle to long-term treatment. Since antipsychotics are often chronically prescribed beginning in childhood, cardiometabolic risk accumulates. An increased susceptibility to antipsychotic-induced weight gain (AIWG) has been repeatedly documented in children, particularly rapid weight gain. Associated cardiometabolic abnormalities include central obesity, insulin resistance, dyslipidemia, and systemic inflammation. Lifestyle interventions and medications such as metformin have been proposed to reduce risk but remain limited in efficacy. Furthermore, antipsychotic medications touted to be weight-neutral in adults can cause substantial weight gain in children. A better understanding of the biological underpinnings of AIWG could inform targeted and potentially more fruitful treatments; however, little is known about the underlying mechanism. As yet, modest genetic studies have nominated a few risk genes that explain only a small percentage of the risk. Recent investigations have begun to explore novel potential mechanisms of AIWG, including a role for gut microbiota and microbial metabolites. This article reviews the problem of AIWG and AP metabolic side effects in pediatric populations, proposed mechanisms underlying this serious side effect, and strategies to mitigate adverse impact. We suggest future directions for research efforts that may advance the field and lead to improved clinical interventions.

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Progress in Genetic Polymorphisms Related to Lipid Disturbances Induced by Atypical Antipsychotic Drugs

Cited by 16 publications

References 152 publications

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children

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