Psychotropic agent thioridazine elicits potent in vitro and in vivo anti-melanoma effects

Jiang, Xiaoshuang; Chen, Zhuo; Shen, Guobo; Jiang, Yong; Wu, Liangjun; Li, Xue; Wang, Guoping; Yin, Tao

doi:10.1016/j.biopha.2017.11.012

Cited by 24 publications

(23 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, four dopamine receptor (DR) inhibitors, belonging to the antipsychotic family of phenothiazines, were among the top hits in our screen (Figure 1B) [19]. Some members of this family of antipsychotics were recently reported to have effects on proliferation, apoptosis, stemness and migration in several cancer types including melanoma [20, 21], ovarian cancer [22, 23], breast cancer [24, 25], cervical and endometrial cancer [26] and lung cancer [27, 28]. Indeed, previous work has shown that DRs are enriched in leukemic and primary TNBC cancer stem-like cells, suggesting that THZ could act through these receptors to limit their expansion [29].…”

Section: Resultsmentioning

confidence: 99%

“…Nonetheless, most of the studies, including our own, have been carried out using immunocompromised mice and it has been established that immune cells greatly modulate the efficacy of traditional therapies. Nevertheless, immunocompetent mouse cancer models were successfully treated with THZ in two different studies, suggesting that the effect on tumor growth is maintained in immunocompetent models [21, 24].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer

et al. 2019

View full text Add to dashboard Cite

Triple-Negative Breast Cancer (TNBC) is an aggressive cancer subtype that is associated with a poor prognosis due to its propensity to form metastases. The receptor tyrosine kinase AXL plays a role in tumor cell dissemination and its expression in breast cancers correlates with poor patient survival. Here, we explored whether already used drugs might elicit a gene signature similar to that seen with AXL knockdown in TNBC cells and which could, therefore, offer an opportunity for drug repurposing. To this end, we queried the Connectivity Map with an AXL gene signature which revealed a class of dopamine receptors antagonists named phenothiazines (Thioridazine, Fluphenazine and Trifluoperazine) typically used as anti-psychotics. We next tested if these drugs, similarly to AXL depletion, were able to limit growth and metastatic progression of TNBC cells and found that phenothiazines are able to reduce cell invasion, proliferation, viability and increase apoptosis of TNBC cells in vitro . Mechanistically, these drugs did not affect AXL activity but instead reduced PI3K/AKT/mTOR and ERK signaling. When administered to mice bearing TNBC xenografts, phenothiazines were able to reduce tumor growth and metastatic burden. Collectively, these results suggest that these antipsychotics display anti-tumor and anti-metastatic activity and that they could potentially be repurposed, in combination with standard chemotherapy, for the treatment of TNBC.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Therefore, the ERα abundance is regulated by different mechanisms acting at both the transcriptional and post-transcriptional levels [10]. Although we did not aim to identify the underlying mechanisms for the ability of mitoxantrone, a topoisomerase II inhibitor that induces DNA damage [28], and of thioridazine, a drug used to treat psychiatric disorders [29], to reduce ERα protein levels, our in silico analysis revealed additional activities for these already FDA-approved drugs that deserve future detailed investigations. Nonetheless, based on the present data and because menadione can reduce the ERα intracellular content [16,17], we conclude that the modulation of the ERα intracellular concentration in BC cells is a robust pharmacological target that can be used also for in silico screenings to fish out drugs affecting the ERα content in BC cells.…”

Section: Discussionmentioning

confidence: 99%

In silico screening for ERα downmodulators identifies thioridazine as an anti-proliferative agent in primary, 4OH-tamoxifen-resistant and Y537S ERα-expressing breast cancer cells

Busonero

Leone

Bianchi

et al. 2018

Preprint

View full text Add to dashboard Cite

Purpose: Most breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (i.e., ICI182,780-ICI).Unfortunately, a high fraction of ET-treated women relapses and become resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using the modulation of the ERα intracellular content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ERα content in BC cells. Methods:We screened in silico more than 60,000 compounds to identify FDA-approved drugs with a gene signature similar to that of ICI. We identified mitoxantrone and thioridazine and tested them in primary, Tam-resistant and genome-edited Y537S ERα-expressing BC cells.Results: Mitoxantrone and thioridazine induced ERα downmodulation and prevented MCF-7 cell proliferation. Interestingly, while mitoxantrone was toxic for normal breast cells, thioridazine showed preferential activity toward BC cells. Thioridazine also reduced the ERα content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ERα-expressing BC cells. Conclusions:We suggest that the modulation of the ERα intracellular concentration in BC cells can also be robustly exploited in in silico screenings to identify anti-BC drugs and further demonstrate a re-purposing opportunity for thioridazine in primary and metastatic ET-resistant BC treatment.

show abstract

“…The method of RNA extraction and quantitative real-time PCR (qRT-PCR) according to the protocol previously described (16). Total RNA was extracted from the cells by Trizol reagent, and then cDNA was synthesized.…”

Section: Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

“…Recently, antipsychotic drugs were found to have an anticancer effect. Phenothiazine compounds such as thioridazine were demonstrated to have the ability to inhibit some cancers such as melanoma (16), breast cancer (17), and colon cancer (18). There is a little study about chlorpromazine's anti-cancer effect.…”

Section: Pelp1 Was a Potential Target Of Antipsychotic Drug Chlorprommentioning

confidence: 99%

PELP1 Suppression Inhibits Gastric Cancer Through Downregulation of c-Src-PI3K-ERK Pathway

Yan

Sun

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

Background: Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), a co-activator of estrogen receptors alpha, was confirmed to be directly associated with the oncogenic process of multiple cancers, especially hormone-dependent cancers. The purpose of our research was to explore the biological function, clinical significance, and therapeutic targeted value of PELP1 in gastric cancer (GC). Methods: The expression status of PELP1 in GC cell lines or tissues was analyzed through bioinformatics data mining. Thirty-six GC tissue chip was applied to demonstrate the results of bioinformatics data mining assayed by immunohistochemical method. The expression status of PELP1 in GC cell lines was also analyzed using western blot. Correlation analysis between PELP1 expression and clinicopathological parameter was performed. Kaplan-Meier survival analysis was applied to analyze the relationship between PELP1 expression and total survival time. Three pairs of siRNA were designed to silence the expression of PELP1 in GC. After PELP1 was silenced by siRNA or activated by saRNA, the growth, plate colony formation, migration and invasion ability of the GC cell or normal gastric epithelium cell line was tested in vitro. Cell cycle was tested by flow cytometry. Nude mice xenograft experiment was performed after PELP1 was silenced. The downstream molecular pathway regulated by PELP1 was explored. Molecular docking tool was applied to combine chlorpromazine with PELP1. The inhibitory effect of chlorpromazine in GC was assayed, then it was tested whether PELP1 was a therapeutic target of chlorpromazine in GC. Results: PELP1 expression was elevated in GC cell lines and clinical GC tissue samples. PELP1 silence by siRNA compromised the malignant traits of GC. PELP1 expression positively correlated with tumor invasion depth, lymph node metastasis, tissue grade, TNM stage, but had no correlation with patient age, sex, tumor size, and tumor numbers. Kaplan-Meier survival analysis revealed high PELP1 expression had a shorter survival period in GC patients after follow-up. Q-PCR and western blot revealed PELP1 suppression in GC decreased expression of the c-Src-PI3K-ERK pathway. It was also implied that chlorpromazine (CPZ) can inhibit the malignant traits of GC and downregulate the expression of PELP1. Yan et al. PELP1 Is an Oncogene in Gastric Cancer Conclusions: In a word, PELP1 is an oncogene in gastric cancer and c-Src-PI3K-ERK pathway activation may be responsible for its tumorigenesis, PELP1 may be a potential therapeutic target of chlorpromazine in GC.

show abstract

Psychotropic agent thioridazine elicits potent in vitro and in vivo anti-melanoma effects

Cited by 24 publications

References 19 publications

AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer

AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer

In silico screening for ERα downmodulators identifies thioridazine as an anti-proliferative agent in primary, 4OH-tamoxifen-resistant and Y537S ERα-expressing breast cancer cells

PELP1 Suppression Inhibits Gastric Cancer Through Downregulation of c-Src-PI3K-ERK Pathway

Contact Info

Product

Resources

About