地塞米松模拟纳米剂型紫杉醇在乳腺癌细胞中的抗癌作用。
Dexamethasone simulates the anticancer effect of nano-formulated paclitaxel in breast cancer cells.
机构信息
Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University, Egypt.
Department of Medical Biophysics, Medical Research Institute, Alexandria University, Egypt.
出版信息
Bioorg Chem. 2020 Jun;99:103792. doi: 10.1016/j.bioorg.2020.103792. Epub 2020 Mar 23.
Although the chemosensitizing effect of Dexamethasone (DEX) and its ability to increase the sensitivity of breast cancer cells to chemotherapy were previously reported, this study aimed to explore how far cotreatment of breast cancer cells with paclitaxel (PTX) and DEX mimics the anticancer effect of nanoformulated PTX. To establish this goal, PTX was nanoformulated with poly (lactic-co-glycolic acid) (PLGA) and the nanoparticles (PTX-NPs) were physically authenticated. Breast cancer cells (MCF-7) were treated with PTX or PTX-NPs in presence or absence of low concentration (10 nM) of DEX. Cells viability (assessed by MTT assay), apoptosis (assessed by flow cytometry) and the expression of PTX resistance gene (TRX1) and PTX metabolizing genes (CYP2C8 and CYP3A4) were investigated. The results showed that nanoformulated PTX was validated by nano-size assessment, increased the anionic surface charge and prober conjugation with the biodegradable carrier (PLGA), as indicated by the FTIR spectroscopy. Initially, the IC value of PTX was 19.3 μg/ml and cotreatment with DEX minimized it to 5.22 μg/ml, whereas PTX-NPs alone inhibited cell proliferation with IC 6.67 μg/ml. Also, in presence of DEX, PTX-NPs further decreased the IC to 5 μg/ml. In parallel, DEX has increased the responsiveness of cells to PTX without potentiating its apoptotic effect. Moreover, the glucocorticoid (with PTX or PTX-NPs) downregulated TXR1 gene by 26% (P < 0.01) and 28.4% (P < 0.05) respectively. Similarly, the mRNA level of CYP3A4 significantly decreased in presence of DEX. The main PTX metabolizing gene CYP2C8, in contrast, was upregulated, especially in cells cotreated with PTX/DEX (P < 0.001). Conclusively, the study reports that cotreatment of breast cancer cells with submolar concentration of DEX acts as similar as the nanoformulated PTX, possibly through its modulatory effects on the expression of the main PTX metabolizing gene (CYP2C8) and downregulating Taxol resistance gene.
尽管地塞米松（DEX）的化疗增敏作用及其增加乳腺癌细胞对化疗敏感性的能力此前已有报道，但本研究旨在探讨乳腺癌细胞同时接受紫杉醇（PTX）和 DEX 治疗在多大程度上模拟了纳米制剂 PTX 的抗癌作用。为了实现这一目标，用聚（乳酸-共-乙醇酸）（PLGA）将 PTX 纳米化，并对纳米颗粒（PTX-NPs）进行物理鉴定。用 PTX 或 PTX-NPs 处理乳腺癌细胞（MCF-7），并在存在或不存在低浓度（10 nM）DEX 的情况下进行处理。通过 MTT 测定法评估细胞活力，通过流式细胞术评估细胞凋亡，以及检测 PTX 耐药基因（TRX1）和 PTX 代谢基因（CYP2C8 和 CYP3A4）的表达。结果表明，通过纳米尺寸评估、增加阴离子表面电荷以及与可生物降解载体（PLGA）的 Prober 缀合，对纳米制剂 PTX 进行了验证，这一点通过傅里叶变换红外光谱（FTIR）得到了证实。最初，PTX 的 IC 值为 19.3 μg/ml，与 DEX 联合治疗将其最小化至 5.22 μg/ml，而单独使用 PTX-NPs 则以 IC 6.67 μg/ml 抑制细胞增殖。此外，在 DEX 存在的情况下，PTX-NPs 进一步将 IC 降低至 5 μg/ml。平行地，DEX 增强了细胞对 PTX 的反应性，而没有增强其凋亡作用。此外，糖皮质激素（与 PTX 或 PTX-NPs 一起）使 TXR1 基因下调了 26%（P<0.01）和 28.4%（P<0.05）。同样，CYP3A4 的 mRNA 水平在 DEX 存在时显著降低。相反，主要的 PTX 代谢基因 CYP2C8 上调，尤其是在 PTX/DEX 共处理的细胞中（P<0.001）。总之，该研究报告称，亚摩尔浓度的 DEX 与乳腺癌细胞共处理的作用类似于纳米制剂 PTX，可能是通过其对主要 PTX 代谢基因（CYP2C8）表达的调节作用和下调紫杉醇耐药基因来实现的。
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