The role of somatostatin and dopamine D2 receptors in endocrine tumors

Gatto, Federico; Hofland, Leo J.

doi:10.1530/erc-10-0334

Cited by 72 publications

(55 citation statements)

References 167 publications

(159 reference statements)

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“…The development of certain small molecules with a high specificity for DR2 or knockdown of DR2 may confer an improved therapeutic prognosis (34,36). However, the DR2 agonist bromocriptin has inhibited proliferation in MCF-7 breast cancer cells (37).…”

Section: Discussionmentioning

confidence: 99%

DR2 blocker thioridazine: A promising drug for ovarian cancer therapy

Yong

Tian

et al. 2017

Oncol Lett

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Abstract. Dopamine receptor 2 (DR2) may be a biomarker for various types of cancer. Ovarian cancer cells overexpress DR2; therefore, blocking DR2 may be a novel treatment strategy for ovarian cancer. Thioridazine, a DR2 blocker, has antineoplastic activity in a variety of cancer cells. In view of the requirement for novel therapeutic agents in ovarian cancer, the present study aimed to determine the potential effects of thioridazine in vitro and in vivo. It was revealed that the DR2 blocker thioridazine induced cell death in a dose-dependent manner in ovarian cancer cells. Thioridazine treatment induced apoptosis and autophagy, which may be attributed to an increased level of reactive oxygen species and associated DNA damage. Additionally, the expression of various proteins increased with oxidative stress, including nuclear factor E2-related factor 2, which is a pivotal transcriptional factor involved in cellular responses to oxidative stress. Heme oxygenase 1, NAPDH quinone dehydrogenase 1 and hypoxia inducible factor-1α and phosphorylated (p)-protein kinase B expression was significantly decreased, and the expression level of p-extracellular signal-related kinases and p-P38 was increased. Using 3-methyl adenine to inhibit autophagy caused the rate of apoptosis to increase. Thioridazine inhibited the growth of SKOV3 xenografts in nude mice. The present study demonstrated that the DR2 blocker thioridazine exhibited anticancer effects in vitro and in vivo, suggesting that thioridazine may be used as a potential drug in ovarian cancer therapy. IntroductionEpithelial ovarian cancer is the leading cause of mortality among gynecological types of cancer. Surgical debulking combined with chemotherapy is the standard therapeutic strategy. However, the relapse rate is high, primarily due to the development of chemotherapy resistance (1), therefore, novel modalities must be explored.Dopamine receptor (DR) expression may be associated with the development of various types of cancer. Patients with schizophrenia who receive DR antagonists have a reduced incidence of cancer of the rectum, colon, prostate and uterine cervix (2,3). Patients with Parkinson's disease, which functionally similar to disease-induced DR antagonism, also have a lower incidence of cancer. It was hypothesized that DR may be a biomarker for cancer (4). Knockdown/blocking of DR2 inhibited the proliferation of cancer cells, including cancer stem cells (5). This suggested that DR2 may be a treatment target for types of cancer that expresses dopamine receptor 2.Thioridazine is a DR2 antagonist and has been clinically approved to treat schizophrenia and other psychotic disorders (6). Of note, thioridazine exhibits anticancer action in breast cancer, leukemia, hepatoma and cervical carcinoma (5,7-9). Ovarian cancer cells express a number of DRs, with the exception of DR3 (10), suggesting that thioridazine may be used to treat ovarian cancer. In the present study, the effects of thioridazine on ovarian cancer were explored in vitro and in vivo. The findings sug...

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Section: Discussionmentioning

confidence: 99%

DR2 blocker thioridazine: A promising drug for ovarian cancer therapy

Yong

Tian

et al. 2017

Oncol Lett

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“…Thioridazine is an antagonist of the dopamine receptor D2 family proteins, and analogues of thioridazine have also exhibited antitumor effects (15), implying the involvement of the dopamine receptor signaling pathway in cancer. Dopamine receptor family proteins have been reported to be correlated with cancer therapy (20,21). Thioridazine may elicit tumor growth inhibition in a dopamine receptor-dependent and -independent manner.…”

Section: Discussionmentioning

confidence: 99%

Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer

et al. 2014

Oncology Reports

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Abstract. Thioridazine, an antipsychotic drug, has been reported to induce apoptosis in various types of cancer cells, with specificity on targeting cancer stem cells (CSCs). However, whether it elicits anticancer effects in gastric cancer has never been reported. In the present study, we examined the ability of thioridazine to induce cell death in the gastric cancer cell lines NCI-N87 and AGS, and detected its in vivo tumor inhibition capacity. Thioridazine elicited cytotoxic effects on NCI-N87 and AGS cells in a dose-dependent manner, and inhibited the colony formation abilitiy of the NCI-N87 and AGS cells. Thioridazine treatment induced nuclear fragmentation, increased the proportion of sub-G1 phase cells, and elevated the percentage of Annexin V-positive cells, suggesting the occurrence of apoptosis. Moreover, thioridazine induced gastric cancer cell apoptosis in a caspase-dependent manner, as shown by a decrease in the precursors of casapse-9, caspase-8 and caspase-3, and by the ability of the caspase inhibitor Z-VAD-FMK to reverse the cytotoxic effect of thioridazine. JC-1 staining further revealed that thioridazine induced gastric cancer cell apoptosis via the mitochondrial pathway. In addition, thioridazine pretreatment inhibited the growth of NCI-N87 cell-derived tumors. The present study demonstrated that the antipsychotic drug thioridazine possesses anti-gastric cancer ability through in vitro and in vivo experiments, suggesting thioridazine as a potential drug in gastric cancer therapy. IntroductionGastric cancer is the fourth most common cancer worldwide with 989,600 new cases diagnosed in 2008, and it is the second leading cause of cancer-related death (1,2). Gastric cancer is either asymptomatic or causes non-specific symptoms at an early stage, and thus the majority of patients present with advanced stage disease at the time of initial diagnosis, leading to the poor prognosis of gastric cancer. Gastric cancer treatment involves surgery, chemotherapy, radiation therapy and their combinations. However, current drugs are confronted with low efficacy due to the high rate of patients at the advanced stage of gastric cancer. Thus, the development of novel effective drugs for gastric cancer therapy is urgently needed.Thioridazine, an antagonist of the dopamine receptor D2 family proteins, was initially developed as an antipsychotic drug, and recently its anticancer function was revealed. Studies have revealed the antiproliferative and apoptosis induction capacities of thioridazine in neuroblastoma, glioma, leukemia, breast cancer, cervical cancer and endometrial cancer (3-6). A gene signature-based approach identified thioridazine as an inhibitor of PI3K/Akt signaling in ovarian cancer cells. It downregulated cell cycle regulators cyclin D1 and CDK4, and upregulated p21, p16 and p-CDC25A, leading to the G0/ G1 phase arrest of the cells (7). Research on cervical and endometrial cancer cells disclosing the involvement of the PI3K/Akt/mTOR pathway in thioridazine-induced apoptosis further supported this fi...

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“…Inhibition of PRL secretion is the most well-known action of dopamine in the anterior pituitary. However, results of recent studies have indicated that the D2 receptor is expressed in 80% of corticotrope adenomas (Lamberts et al 1980, Pivonello et al 2004, Gatto & Hofland 2011. The D2 receptor is not negatively regulated by cortisol (de Bruin et al 2009).…”

Section: Dopamine Agonistsmentioning

confidence: 99%

Treatment of Cushing's disease: a mechanistic update

Cuevas‐Ramos¹,

Fleseriu²

2014

Journal of Endocrinology

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Cushing's disease (CD) is characterized by an ACTH-producing anterior corticotrope pituitary adenoma. If hypothalamus-pituitary-adrenal (HPA) axis physiology is disrupted, ACTH secretion increases, which in turn stimulates adrenocortical steroidogenesis and cortisol production. Medical treatment plays an important role for patients with persistent disease after surgery, for those in whom surgery is not feasible, or while awaiting effects of radiation. Multiple drugs, with different mechanisms of action and variable efficacy and tolerability for controlling the deleterious effects of chronic glucocorticoid excess, are available. The molecular basis and clinical data for centrally acting drugs, adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are reviewed, as are potential novel molecules and future possible targets for CD treatment. Although progress has been made in the understanding of specific corticotrope adenoma receptor physiology and recent clinical studies have detected improved effects with a combined medical therapy approach, there is a clear need for a more efficacious and better-tolerated medical therapy for patients with CD. A better understanding of the molecular mechanisms in CD and of HPA axis physiology should advance the development of new drugs in the future.

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The role of somatostatin and dopamine D2 receptors in endocrine tumors

Cited by 72 publications

References 167 publications

DR2 blocker thioridazine: A promising drug for ovarian cancer therapy

DR2 blocker thioridazine: A promising drug for ovarian cancer therapy

Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer

Treatment of Cushing's disease: a mechanistic update

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