Nanoenabled Intracellular Calcium Bursting for Safe and Efficient Reversal of Drug Resistance in Tumor Cells
Nanoenabled Intracellular Calcium Bursting for Safe and Efficient Reversal of Drug Resistance in Tumor Cells
复制标题
纳米细胞内钙爆发可安全有效地逆转肿瘤细胞的耐药性
DOI：
10.1021/acs.nanolett.0c03042
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发表时间：
2020-11-11
期刊：
影响因子：
10.8
通讯作者：
Shi, Jinjin
中科院分区：
文献类型：
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作者：
Liu, Junjie;Zhu, Chunyu;Shi, Jinjin
肿瘤的多药耐药（MDR）是临床化疗失败的主要原因。在此，我们报告了一种简单而通用的肿瘤靶向“钙离子纳米发生器”（TCaNG），通过诱导细胞内Ca 2+爆发来逆转耐药性。因此，TCaNG可以诱导肿瘤细胞酸性溶酶体中的Ca'爆破，然后根据以下机制逆转耐药性：（i）Ca 2+特异性地积聚在线粒体中，抑制细胞呼吸并缓解肿瘤缺氧，从而通过下调HIF-1 α表达来抑制P-糖蛋白的生物合成。(ii)Ca 2+爆发引起的呼吸抑制会阻止细胞内ATP的产生，从而进一步导致P-gp功能丧失。结果表明，TCaNG可使DOX对MCF-7/ADR细胞的IC 50降低约30倍，使耐药肿瘤的增殖降低约13倍，且无明显副作用。这种简单、安全、有效的“Ca 2+爆发”策略在肿瘤治疗中具有临床应用的潜力。
Multidrug resistance (MDR) of a tumor is the main cause of failure of clinical chemotherapy. Herein, we report a simple, yet versatile, tumor-targeting "calcium ion nanogenerator" (TCaNG) to reverse drug resistance by inducing intracellular Ca2+ bursting. Consequently, the TCaNG could induce Ca' bursting in acidic lysosomes of tumor cells and then reverse drug resistance according to the following mechanisms: (i) Ca2+ specifically accumulates in mitochondria, suppressing cellular respiration and relieving tumor hypoxia, thus inhibiting P-glycoprotein biosynthesis by downregulating HIF-la expression. (ii) Ca2+-bursting-induced respiratory depression blocks intracellular ATP production, which further leads to the P-gp incompetence. As a result, the TCaNG could decrease the IC50 of DOX to MCF-7/ADR cells by approximately 30 times and reduce the proliferation of drug-resistant tumors by approximately 13 times without obvious side effects. This simple, safe, and effective "Ca2+ bursting" strategy holds the potential for clinical application in tumor treatment.