Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen

Wang, Lijie; Li, Jian; Hao, Fangran; Yin, Yuan; Li, Jingyun; Lu, Wei; Zhou, Tianyan

doi:10.1038/aps.2016.39

Cited by 47 publications

(33 citation statements)

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“…[64][65][66][67] Proliferation is integral to the development and maintenance of the placenta, and alterations in trophoblast proliferation have been implicated in preeclampsia. A, Schematic representation of GR binding sites either overlapping or in close proximity to the chromosomal location of SERPINE1.…”

Section: Discussionmentioning

confidence: 99%

“…Reductions in the proliferation rate represent another mechanism by which the rate of wound healing may be reduced following cancer cell types. [64][65][66][67] Proliferation is integral to the development and maintenance of the placenta, and alterations in trophoblast proliferation have been implicated in preeclampsia. 68 One recent study demonstrated decreased rates of proliferation of EVTs for women with preeclampsia.…”

Section: Discussionmentioning

confidence: 99%

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Glucocorticoid signaling regulates cell invasion and migration in the human first‐trimester trophoblast cell line Sw.71

Kisanga

Tang

Guller

et al. 2018

American J Rep Immunol

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glucocorticoid signaling regulates cell invasion and migration in the human first‐trimester trophoblast cell line Sw.71

Kisanga

Tang

Guller

et al. 2018

American J Rep Immunol

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“…D2DR antagonists have been used as adjuvants of chemotherapy drugs for cancer therapy [12] , and the anti-cancer effects of DEX for drug-resistant and metastatic cancer has been documented several times [6,7,[9][10][11] . Moreover, in our previous studies [6,7] , DEX exerted a better anti-cancer effect than traditional chemotherapeutics such as gemcitabine and tamoxifen, and the effect might be further improved when combined with other agents [7] . These prior studies prompted us to investigate the anti-cancer effects of DEX in combination with SUL as well as the underlying mechanisms in drug-resistant and metastatic breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Dexamethasone (DEX) is a synthetic glucocorticoid that is frequently used in the clinic. Several published studies have demonstrated the anti-cancer effects of DEX as a single agent [6][7][8][9][10][11] . For estrogen receptor positive (ER+) breast cancer, DEX can significantly antagonize the systemic estrogens by the glucocorticoid receptor-mediated activation of estrogen sulfotransferase, which results in inhibition of breast cancer [8] .…”

Section: Introductionmentioning

confidence: 99%

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer

Yao

Xue

et al. 2017

Acta Pharmacol Sin

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Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg·d) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg·d) and DEX (8 mg·kg·d) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.

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“…Dexamethasone (DEX) is a type of synthetic glucocorticoid that is widely used in the clinical setting. Several pre-vious studies have demonstrated the anti-cancer efficacy of DEX in xenograft breast tumor or other tumor models based on its inhibitory effect on active estrogens in the circulation and regulation of anti-inflammatory cytokines or other factors related to tumor progression [3][4][5][6][7][8][9] . In our previous studies, DEX had a greater suppression effect than general chemotherapeutic drugs, such as epirubicin and gemcitabine, in breast cancer treatment [4,10] .…”

Section: Introductionmentioning

confidence: 99%

Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model

Chen

Yao

et al. 2017

Acta Pharmacol Sin

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Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid E equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an E equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

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Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen

Abstract: DEX suppresses the growth of A549 xenograft tumors via inducing EST and decreasing estradiol levels in tumor tissues, suggesting that DEX may be used as anti-estrogenic agent for the treatment of NSCLC.

Cited by 47 publications

References 47 publications

Glucocorticoid signaling regulates cell invasion and migration in the human first‐trimester trophoblast cell line Sw.71

Glucocorticoid signaling regulates cell invasion and migration in the human first‐trimester trophoblast cell line Sw.71

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer

Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model

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