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Miconazole Triggers Various Forms of Cell Death in Human Breast Cancer MDA-MB-231 Cells

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Miconazole Triggers Various Forms of Cell Death in Human Breast Cancer MDA-MB-231 Cells ORIGINAL ARTICLES School of Pharmacy1, Scientific Research Center2, Bengbu Medical College, Bengbu, Anhui, China Miconazole triggers various forms of cell death in human breast cancer MDA-MB-231 cells CHENGZHU WU1,#,*, MEIJIA GAO1,#, LIN SHEN2, BOHAN LI1, XIANGJIAN BAI1, JIAHUI GUI1, HONGMEI LI1, QIANG HUO1, TAO MA1,* Received October 21, 2018, accepted November 26, 2018 *Corresponding authors: Cheng-Zhu Wu, Tao Ma, School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China [email protected]; [email protected] #These authors contributed equally to this work. Pharmazie 74: 290-294 (2019) doi: 10.1691/ph.2019.8812 In recent years, “drug repurposing” has become an important approach and focus of studies on anti-tumor drug research and development (R&D). As one of the first-generation broad-spectrum imidazole anti-fungal drugs, miconazole (MCZ) exhibits anti-tumor effects in addition to its anti-fungal effect. However, no report has focused on examining the effect of MCZ on the proliferation and cell-death of human breast cancer MDA-MB-231 cells. MCZ significantly inhibited the proliferation of MDA-MB-231 cells in a concentration- and time-dependent manner. We also observed that MCZ induced both apoptosis and necroptosis in MDA-MB-231 cells. Transmission elec- tron microscopy showed submicroscopic structures in these cells, which correspond to necrotic features, in addition to the characteristic features of apoptosis. Pretreatment of cells with z-VAD-fmk, an apoptosis inhibitor or Nec-1, a necroptosis inhibitor, significantly increased their viability compared with MCZ treatment. The initial mechanism of MCZ-mediated cell death in human breast cancer MDA-MB-231 cells involves an increase in the Bax/Bcl-2 ratio, downregulation of apoptosis induced by Akt and p-Akt-473, a simultaneous upregulation of the receptor-interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) protein expression, and ROS production to induce necroptosis. Our results suggest that MCZ may be a potential lead compound for the development of anti-breast cancer drugs. 1. Introduction and hence the anti-tumor effects and corresponding mechanisms Results of recently-performed global cancer surveys have shown of metformin, thalidomide, berberine and bilobalide have been that despite advances in therapeutics, the incidence of breast cancer revealed (Matthews et al. 2003; Rizos et al. 2013; Tillhon et al. remains high, which poses a serious threat to women’s health and life; 2012; Zhi et al. 2016). As one of the first-generation broad-spec- about 15% of the cases are of triple-negative breast cancer (TNBC) trum antifungal drugs for treating fungal infections in crops and (Ferlay et al. 2015; Loi et al. 2013; Siegel et al. 2017). TNBC is a humans, miconazole (MCZ) can be administered externally, orally, breast cancer that does not have estrogen receptor (ER), progesterone and intravenously (Fig. 1A) (Garcia-Cuesta et al. 2014; Heeres et receptor (PR), and human epidermal growth factor receptor-2 (Her-2). al. 2010). According to a few reports, MCZ also has been shown TNBC patients generally show an early onset of cancer and are prone to exhibit antitumor effect via the induction of death receptor-me- to recurrence and metastasis. Moreover, there is a lack of effective diated apoptosis in bladder cancer cells (Yuan et al. 2017). In this drugs and standardized treatment guidelines (Hyslop et al. 2013). study, we investigated the effects of MCZ on cell proliferation and Programmed cell death (PCD) is a cellular mechanism operating at cell death to provide a theoretical basis for future research using the crossroads of multiple diseases and investigation into the regula- the TNBC cell line MDA-MB-231 as a model. tion of the same is important for exploring new disease treatments. Studies have shown that in addition to PCD by apoptosis and auto- 2. Investigations and results phagy, necrosis can be also programmed, and this process is termed as necroptosis (Degterev et al. 2005). Although chemotherapeutics 2.1. MCZ inhibits the proliferation of human breast such as paclitaxel and doxorubicin show positive effects in clinical cancer MDA-MB-231 cells application, tumor cells can gradually develop drug resistance, To understand the anti-breast cancer activity of MCZ, we examined which is characterized by the inhibition of the apoptotic pathway, the viability of MDA-MB-231 cells, treated with different concen- eventually reducing the efficacy of these chemotherapeutics (Ateba trations (0–40 μM) of MCZ for 24, 48, and 72 h, using MTT assay. et al. 2018; Hanahan et al. 2011; Holohan et al. 2013). Different The results of the dose-effect curve showed that the viability of cell death pathways operate via different molecular mechanisms, MDA-MB-231 cells gradually decreased with an increase in MCZ and the resistance of tumor cells to apoptosis generally has no effect concentration and a prolonged duration of action, and the maximal on other cell death pathways. Interestingly, the inhibition of apop- inhibitory concentration (IC50) values of MCZ at 24, 48, and 72 h tosis induced by anti-cancer drugs correspondingly increases the were 21.40, 17.62, and 8.71 μM, respectively (Fig. 1B). According proportion of tumor cells that die through non-apoptotic pathways to the results of MTT assay, we selected 1.0, 2.0, and 4.0 μM (Amaravadi et al. 2007; Buytaert et al. 2006). concentrations of MCZ for treatment of MDA-MB-231 cells for 5 Drug repurposing has become a major approach and research focus days and observed that MCZ treatment could significantly inhibit for new drug R&D because of its high safety, shortened develop- the formation of cell colonies at these concentrations (*P <0.05 ment cycle, and clinically confirmed pharmacokinetic properties and **P <0.01) (Fig. 1C and D). These results indicated that MCZ (Chong et al. 2007). In recent years, great progress has been treatment exerted an anti-proliferative effect on MDA-MB-231 achieved by drug repurposing for anti-tumor drug development, cells in a concentration- and time-dependent manner. 290 Pharmazie 74 (2019) ORIGINAL ARTICLES Fig. 3: MCZ induced apoptosis in MDA-MB-231 cells that is dependent of caspase acitivity. (A) Cell viability following treatment with MCZ (40 μM) with or without 1 h pre-treatment with z-VAD (20 μM), as analyzed by the MTT assay. (B) Annexin V-FITC/PI analysis following treatment with MCZ alone Fig. 1: Anti-proliferation activity of MCZ on human breast cancer MDA-MB-231 or with z-VAD pre-treatment. cells. (A) The structure of miconazole. (B) Cytotoxicity of MCZ was ana- lyzed by the MTT assay. (C) The colony-forming capability was analyzed using a colony fornation assay after treatment with low concentration of transmission electron microscopy. The cells treated with MCZ (40 MCZ. (D) Quantification of colony-forming capability of MDA-MB-231 cells inhibited by MCZ. * P <0.05 and ** P <0.01 compared with the control. μM) exhibited morphological characteristics of apoptosis, such as chromatin margination and nuclear pyknosis in massive cells (Fig. 2C). In addition, with an increase in MCZ concentration, the expression levels of Akt, p-Akt-473 and anti-apoptotic protein 2.2. MCZ induces apoptosis in MDA-MB-231 cells Bcl-2 decreased, and the expression levels of Bax, a pro-apoptotic To further investigate the role of MCZ in inducing MDA-MB- protein, gradually increased in the MCZ-treated cells (Fig. 2D). 231 cell death, we stained the cells with PI and performed flow Thereafter, we compared the differences in viability between the cytometry for detection of cell death. The results of PI staining/ cells subjected to MCZ treatment alone or a combined treatment flow cytometry were consistent with the MTT results; the death with MCZ and a broad-spectrum caspase inhibitor, z-VAD-fmk rate of MDA-MB-231 cells gradually increased with an increase by using MTT assay. As shown in Fig. 3A, the cell viability after 24 h treatment with MCZ (40 μM) alone was 54.48 %, while it increased to 78.9 % after the combined treatment with MCZ and z-VAD-fmk. Next, we verified the above results with Annexin V/PI staining using flow cytometry, which showed that the viability of the cells subjected to the combined treatment of MCZ and z-VAD –fmk combination was significantly higher than that of the cells treated with MCZ alone, indicating that the MCZ-induced cell Fig. 2: MCZ induced apoptosis in human breast cancer MDA-MB-231 cells. (A) Flow cytometric analysis of cell death after treatment with various concen- trations of MCZ using PI staining. (B) MDA-MB-231 cell was treated with MCZ for 24 h, subjected to DAPI staining and visualized using fluorescence microscopy. Red arrowheads indicated apoptotic cells. (C) Electron micros- copy of MDA-MB-231 cells treatment with DMSO or MCZ for 24 h. (D) Western blot analyses of Akt, p-Akt, Bax and Bcl-2 levels in MDA-MB-231 cells, using GAPDH as the internal control. in MCZ concentration (Fig. 2A). The cell death rates following the 24 h treatment of MCZ at different concentrations (0–40 μM) were 5.7 %, 13.9 %, and 41.8 %, respectively. Moreover, DAPI staining revealed that with increasing concentrations of MCZ, chromatin showed a higher incidence of pyknosis, as is evident Fig. 4: MCZ induced necroptosis in human breast cancer MDA-MB-231 cells. from increased intensity of DAPI staining, and also some of (A) Eletron microscopy of cells after treating with DMSO or MCZ. (B) the nuclei showed characteristics of apoptosis such as nuclear Cell viability following treatment with MCZ (40 μM) with or without 1 h fragmentation and disintegration (Fig. 2B). To further confirm pre-treatment with Nec-1 (20 μM), as analyzed by the MTT assay.
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