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

Abstract

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.

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

“…The detailed inhibitory effects of DEX on a MCF-7/Adr xenograft tumor was published elsewhere [4] . Tumor growth after different dose regimens is shown in Figure 2B.…”

“…The integrated PK/PD model of DEX was developed on the assumption that DEX exerted its tumor inhibitory efficacy through suppressing the proliferation of tumor cells rather than stimulating their eradication, which was based on its main mechanisms of inactivating estrogens in the circulation or regulating the anti-inflammatory cytokines or other factors related to tumor progression [3][4][5][6][7][8][9] . The drug potency of DEX was characterized by an E max equation, and the E max value was assumed as 1, which does not agree with Yuan et al's study in which the drug effect was modeled as a linear correlation to the concentration of DEX [10] .…”

“…The detailed PD study was published earlier [4] . In terms of methods, 2×10 6 MCF-7/Adr cells were suspended in 200 μL of FBS-free medium and subcutaneously injected into the right flanks of mice to establish an orthotopic breast cancer xenograft model.…”

“…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] . Therefore, it may be of great significance to study the pharmacokinetic and pharmacodynamic processes of DEX in xenograft breast tumor models in detail.…”

Kanser hücreleri üzerine Origanum minutiflorum’un Sitotoksik Etkisinin Araştırılması

“…Bu amaçla in vivo veya in vitro meme kanser modellerinde birçok hücre dizini kullanılmaktadır. İn vitro çalışmalarda kullanılan MCF-10A, MCF-7, SK-BR-3, MDA-MB-231, MDA-MB-436 ve 4T1 hücre dizinleri bunlardan bazılarıdır [9][10][11][12][13]. Bu hücre dizinleri meme dokusu kaynaklı adenokarsinom olup östrojen reseptörleri açısından farklılık göstermektedirler.…”