Thioridazine inhibits angiogenesis and tumor growth by targeting the VEGFR-2/PI3K/mTOR pathway in ovarian cancer xenografts

Park, Mi Sun; Dong, Seung Myung; Kim, Boh-Ram; Seo, Seung Hee; Kang, Sokbom; Lee, Eun‐Ju; Lee, Seung‐Hoon; Rho, Seung Bae

doi:10.18632/oncotarget.2063

Cited by 55 publications

(58 citation statements)

References 20 publications

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“…Consistent with the expression of HIF1α, VEGF was downregulated. Inhibition of angiogenesis may result in anticancer efficacy (30). Overexpression or hyper-activation of Nrf2 may participate in tumorigenesis.…”

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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“…This approach has been particularly successful with non-steroidal antiinflammatory drugs (NSAIDs) and antidiabetics such as metformin (1,2). Phenothiazine-derived antipsychotic drugs such as thioridazine and chlorpromazine exhibit anticarcinogenic activity in several different cancer cell lines (3–9). More recent studies have demonstrated that penfluridol, another antipsychotic drug, also inhibits breast and pancreatic cancer cell growth (9,10).…”

Section: Introductionmentioning

confidence: 99%

Penfluridol Represses Integrin Expression in Breast Cancer through Induction of Reactive Oxygen Species and Downregulation of Sp Transcription Factors

Hedrick

Safe

2017

Molecular Cancer Therapeutics

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It was recently demonstrated the penfluridol inhibited breast tumor growth and metastasis and this was associated with downregulation of α6- and β4-integrins. In this study, we observed the penfluridol induced reactive oxygen species (ROS) and this was the primary mechanism of action. Penfluridol-mediated growth inhibition, induction of apoptosis, and inhibition breast cancer cell migration was attenuated after cotreatment with glutathione (GSH). Penfluridol also downregulated Sp transcription factors Sp1, Sp3 and Sp4 through epigenetic downregulation of cMyc and cMyc-regulated microRNAs (miR-27a and miR-20a/miR-17) and induction of the miR-regulated Sp transcriptional repressors ZBTB10 and ZBTB4. α6- and β4-Integrins as well as α5- and β1-integrin are Sp-regulated genes that are also coregulated by the orphan nuclear receptor NR4A1 and these integrins can be targeted by agents such as penfluridol that suppress Sp1, Sp3 and Sp4 and also by NR4A1 antagonists.

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“…4,5 Thioridazine (Thio), a phenothiazine derivative, is a piperidine antipsychotic drug that was recently found to inhibit cancer cell growth. [6][7][8] Doxorubicin (Dox), an anthracycline antibiotic, is one of the most widely applied anticancer drugs for various malignancies, including breast, prostate, and colon cancers. [9][10][11][12] However, serious side effects, such as the dose-dependent cardiotoxicity, myelosuppression, and nephrotoxicity, markedly limit its clinical use.…”

Section: Introductionmentioning

confidence: 99%

Codelivery of thioridazine and doxorubicin using nanoparticles for effective breast cancer therapy

Jin¹,

Zou²,

Luo³

et al. 2016

IJN

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Cancer chemotherapy can benefit from the combination of different anticancer drugs. Here, we prepared doxorubicin (Dox)- and thioridazine (Thio)-coloaded methoxy poly(ethylene glycol)-poly( l -lactic acid) (MPEG-PLA) nanoparticles (NPs) for breast cancer therapy. These NPs have an average particle size of 27 nm. The drug loading efficiencies of Thio and Dox are 4.71% and 1.98%, respectively. Compared to the treatment of Thio or Dox alone, the combination of Thio and Dox exhibited a synergistic effect in inhibiting the growth of 4T1 breast cancer cells in vitro. In addition, the Thio- and Dox-coloaded MPEG-PLA NPs could efficiently suppress the growth of breast cancer cells in vivo. This study suggests that Thio- and Dox-coloaded MPEG-PLA NPs might have potential applications in breast cancer treatment.

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Thioridazine inhibits angiogenesis and tumor growth by targeting the VEGFR-2/PI3K/mTOR pathway in ovarian cancer xenografts

Cited by 55 publications

References 20 publications

DR2 blocker thioridazine: A promising drug for ovarian cancer therapy

DR2 blocker thioridazine: A promising drug for ovarian cancer therapy

Penfluridol Represses Integrin Expression in Breast Cancer through Induction of Reactive Oxygen Species and Downregulation of Sp Transcription Factors

Codelivery of thioridazine and doxorubicin using nanoparticles for effective breast cancer therapy

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