The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia
The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia
复制标题
PI3K/mTOR双重抑制剂BEZ235抑制增殖和迁移并逆转急性髓系白血病的多药耐药性
DOI：
10.1038/aps.2016.121
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发表时间：
2017-03-01
影响因子：
8.2
通讯作者：
Wang, Xiu-Ju
中科院分区：
文献类型：
--
作者：
Deng, Lan;Jiang, Ling;Wang, Xiu-Ju
PI3K/Akt/mTOR 通路的异常激活会促进恶性细胞的增殖，并可能导致各种恶性肿瘤（包括急性髓系白血病 (AML)）对化疗产生耐药性。化疗耐药是 AML 复发的主要原因。 RAD001（依维莫司）已用于 AML 诱导化疗方案的第 1 日和第 7 日，其毒性可接受，可改善常规化疗治疗。 PI3K 和 mTOR 双重抑制剂克服了雷帕霉素及其衍生物的一些固有缺点。在本研究中，我们在体外评估了 PI3K/mTOR 双重抑制剂 BEZ235 对多重耐药 AML 细胞系 HL-60/VCR 和 K562/ADR 的影响。 BEZ235剂量依赖性地抑制HL-60/VCR和K562/ADR细胞的活力，IC50值分别为66.69和71.44 nmol/L。 BEZ235 (25-100 nmol/L)剂量依赖性地抑制两种AML细胞系的迁移，并且还显着提高两种AML细胞系对VCR和ADR的敏感性。用BEZ235处理后，HL-60/VCR细胞中的miR-1-3p水平显着增加。使用 TargetScan 分析和荧光素酶测定，我们发现 miR-1-3p 靶向 BAG4、EDN1 和 ABCB1（细胞凋亡、迁移和多药耐药性的关键调节因子），并显着降低了两种 AML 细胞系中它们的水平。用miR-1-3p-AMO转染HL-60/VCR和K562/ADR细胞以抑制miR-1-3p可以逆转BEZ235的抗增殖作用。总之，PI3K/mTOR 双重抑制剂 BEZ235 通过增加 miR-1-3p 并随后下调 BAG4、EDN1 和 ABCB1 有效地使 AML 细胞化疗增敏。
Aberrant activation of the PI3K/Akt/mTOR pathway contributes to the proliferation of malignant cells, and may confer resistance to chemotherapy in various malignancies, including acute myeloid leukemia (AML). Chemoresistance is the major reason for relapse in AML. RAD001 (everolimus) has been used at d1 and d7 of an induction chemotherapy regimen for AML, which has acceptable toxicity and may improve conventional chemotherapeutic treatment. Dual inhibitors of PI3K and mTOR overcome some of the intrinsic disadvantages of rapamycin and its derivatives. In this study, we evaluated the effects of BEZ235, a PI3K/mTOR dual inhibitor, on the multidrug-resistant AML cell lines HL-60/VCR and K562/ADR in vitro. BEZ235 dose-dependently inhibited the viability of HL-60/ VCR and K562/ADR cells with the IC50 values of 66.69 and 71.44 nmol/L, respectively. BEZ235 (25-100 nmol/L) dose-dependently inhibited the migration of the two AML cell lines, and it also significantly sensitized the two AML cell lines to VCR and ADR. After treatment with BEZ235, the miR-1-3p levels were markedly increased in HL-60/VCR cells. Using TargetScan analysis and luciferase assays, we showed that miR-1-3p targeted BAG4, EDN1 and ABCB1, the key regulators of cell apoptosis, migration and multidrug resistance, and significantly decreased their levels in the two AML cell lines. Transfection of HL-60/VCR and K562/ADR cells with miR-1-3p-AMO to inhibit miR-1-3p could reverse the anti-proliferation effects of BEZ235. In conclusion, the PI3K/mTOR dual inhibitor BEZ235 effectively chemosensitizes AML cells via increasing miR-1-3p and subsequently down-regulating BAG4, EDN1 and ABCB1.