Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts

Gwynne, William D.; Hallett, Robin; Girgis-Gabardo, Adele; Bojović, Bojana; Dvorkin‐Gheva, Anna; Aarts, Craig; Dias, Kay; Bane, Anita; Hassell, John A.

doi:10.18632/oncotarget.16646

Cited by 35 publications

(45 citation statements)

References 70 publications

(89 reference statements)

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“…NOR acts as a CAD to inhibit autophagy. Tricyclic antidepressants have been shown to eliminate breast cancer cells by interfering with serotonin transport 37 , and GBM cells by promoting autophagy 38 . While tricyclic antidepressants inhibit serotonin and norepinephrine re-uptake transporters and act as antidepressants, they can also function as cationic amphiphilic drugs (CADs) that interfere with lysosomal function 39,40 .…”

Section: Resultsmentioning

confidence: 99%

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

et al. 2020

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Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of nonfunctional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.

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Section: Resultsmentioning

confidence: 99%

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

et al. 2020

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“…190,191 Of the 280 drugs listed in the ReDO database, 40 affect ion channel function. For example, one potassium channel, Kir4.1, can be blocked via commonly prescribed SSRI, which has been shown to have antitumor effects in colon 192 and breast 193 cancers.…”

Section: Bioelectricity and Metastasis 123mentioning

confidence: 99%

Bioelectric Control of Metastasis in Solid Tumors

2019

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As the leading cause of death in cancer, there is an urgent need to develop treatments to target the dissemination of primary tumor cells to secondary organs, known as metastasis. Bioelectric signaling has emerged in the last century as an important controller of cell growth, and with the development of current molecular tools we are now beginning to identify its role in driving cell migration and metastasis in a variety of cancer types. This review summarizes the currently available research for bioelectric signaling in solid tumor metastasis. We review the steps of metastasis and discuss how these can be controlled by bioelectric cues at the level of a cell, a population of cells, and the tissue. The role of ion channel, pump, and exchanger activity and ion flux is discussed, along with the importance of the membrane potential and the relationship between ion flux and membrane potential. We also provide an overview of the evidence for control of metastasis by external electric fields (EFs) and draw from examples in embryogenesis and regeneration to discuss the implications for endogenous EFs. By increasing our understanding of the dynamic properties of bioelectric signaling, we can develop new strategies that target metastasis to be translated into the clinic.

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“…Finding the receptors responsible for these effects may be important but complicated, as thioridazine is known to bind other GPCRs (44). Interestingly, antagonism of serotonergic receptors has been shown to reduce breast cancer growth (54). Important roles of adrenergic receptors in promoting progression and angiogenesis of prostate cancer have also been recently reported (55,56).…”

Section: Thioridazine Inhibits Self-renewal and Proliferationmentioning

confidence: 99%

Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G1 arrest independent of DRD2

Tegowski

Fan

Baldwin

2018

Journal of Biological Chemistry

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Thioridazine is an antipsychotic that has been shown to induce cell death and inhibit self-renewal in a broad spectrum of cancer cells. The mechanisms by which these effects are mediated are currently unknown but are presumed to result from the inhibition of dopamine receptor 2 (DRD2). Here we show that the self-renewal of several, but not all, triple-negative breast cancer cell lines is inhibited by thioridazine. The inhibition of self-renewal by thioridazine in these cells is mediated by DRD2 inhibition. Further, we demonstrate that DRD2 promotes self-renewal in these cells via a STAT3- and IL-6-dependent mechanism. We also show that thioridazine induces a G arrest and a loss in cell viability in all tested cell lines. However, the reduction in proliferation and cell viability is independent of DRD2 and STAT3. Our results indicate that although there are cell types in which DRD2 inhibition results in inhibition of STAT3 and self-renewal, the dramatic block in cancer cell proliferation across many cell lines caused by thioridazine treatment is independent of DRD2 inhibition.

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Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts

Cited by 35 publications

References 70 publications

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

Bioelectric Control of Metastasis in Solid Tumors

Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G1 arrest independent of DRD2

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