广西医学

目的探讨伊曲康唑对三阴性乳腺癌（TNBC）细胞铁死亡的诱导作用及其可能机制。方法（1）将MDA⁃MB⁃231细胞和BT⁃549细胞分别分为对照组及不同浓度药物组，分别加入完全培养基、不同浓度（2 μmol/L、4 μmol/L、8 μmol/L、16 μmol/L、32 μmol/L）的伊曲康唑处理48 h后，采用CCK⁃8法检测细胞活性，并计算伊曲康唑的半数抑制浓度（IC50）。（2）将MDA⁃MB⁃231细胞和BT⁃549细胞分为对照组（加入完全培养基）、伊曲康唑组（5 μmol/L的伊曲康唑）、伊曲康唑+铁死亡抑制剂组（分别加入5 μmol/L的伊曲康唑和Ferrostatin⁃1）与铁死亡抑制剂组（加入5 μmol/L的Ferrostatin⁃1）。检测对照组和伊曲康唑组两种细胞的脂质过氧化物水平和谷胱甘肽水平；检测4组细胞活性，以及溶质载体家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）的蛋白表达水平。结果（1）MDA⁃MB⁃231细胞和BT⁃549细胞的活性随伊曲康唑浓度的增加而降低，伊曲康唑对MDA⁃MB⁃231细胞和BT⁃549细胞的IC50分别为4.648 μmol/L和4.612 μmol/L。（2）伊曲康唑组MDA⁃MB⁃231细胞和BT⁃549细胞的谷胱甘肽水平较对照组降低，脂质过氧化物水平较对照组升高（P<0.05）。（3）与对照组比较，伊曲康唑组MDA⁃MB⁃231细胞和BT⁃549细胞的活性、SLC7A11及GPX4蛋白表达水平降低（P<0.05）；与伊曲康唑组比较，伊曲康唑+铁死亡抑制剂组MDA⁃MB⁃231细胞和BT⁃549细胞的活性、SLC7A11和GPX4蛋白表达水平升高（P<0.05）。结论伊曲康唑可能通过调节SLC7A11/GPX4轴来诱导细胞铁死亡，从而抑制TNBC细胞的增殖。

Objective To investigate the induction of itraconazole on ferroptosis in triple⁃negative breast cancer (TNBC) cells and its possible mechanism. Methods (1) MDA⁃MB⁃231 cell and BT⁃549 cell were assigned to control group or drug with different concentrations groups, respectively, and complete medium and itraconazole with different concentrations (2 μmol/L, 4 μmol/L, 8 μmol/L, 16 μmol/L, 32 μmol/L) were added for a 48⁃hour treatment, respectively, after then the CCK⁃8 method was used to detect cellular activity, and half inhibitory concentration (IC50) of itraconazole was calculated. (2) MDA⁃MB⁃231 cell and BT⁃549 cell were assigned to control group (adding complete medium), itraconazole group (adding itraconazole of 5 μmol/L), itraconazole+ferroptosis inhibitor group (adding itraconazole and Ferrostatin⁃1 of 5 μmol/L, respectively), or ferroptosis inhibitor group (adding Ferrostatin⁃1 of 5 μmol/L). The levels of lipid peroxide and glutathione of the two cells in the control group and the itraconazole group, cellular activity of the four groups, and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) were detected. Results (1) The activities of MDA⁃MB⁃231 and BT⁃549 cells decreased with the increase of itraconazole concentration. IC50 of itraconazole on MDA⁃MB⁃231 and BT⁃549 cells was 4.648 μmol/L and 4.612 μmol/L, respectively. (2) Glutathione level of MDA⁃MB⁃231 cell and BT⁃549 cell in the itraconazole group was decreased as compared with the control group, whereas lipid peroxide level was elevated as compared with the control group (P<0.05). (3) Compared with the control group, the activities of MDA⁃MB⁃231 and BT⁃549 cells, and protein expressions of SLC7A11 and GPX4 in the itraconazole group were decreased (P<0.05). Compared with the itraconazole group, the activities of MDA⁃MB⁃231 and BT⁃549 cells, and protein expressions of SLC7A11 and GPX4 in the itraconazole+ferroptosis inhibitor group were elevated (P<0.05). Conclusion Itraconazole may induce cellular ferroptosis by regulating SLC7A11/GPX4 axis, thereby inhibiting the proliferation of TNBC cells.