Sequence-Dependent Synergistic Inhibition of Human Glioma Cell Lines by Combined Temozolomide and miR-21 Inhibitor Gene Therapy
Sequence-Dependent Synergistic Inhibition of Human Glioma Cell Lines by Combined Temozolomide and miR-21 Inhibitor Gene Therapy
复制标题
替莫唑胺和 miR-21 抑制剂基因联合治疗对人胶质瘤细胞系的序列依赖性协同抑制。
DOI：
10.1021/mp3002039
复制
发表时间：
2012-09-01
影响因子：
4.9
通讯作者：
Kang, Chunsheng
中科院分区：
文献类型：
--
作者：
Qian, Xiaomin;Ren, Yu;Kang, Chunsheng
在肿瘤治疗中，下调microRNA-21(miR-21)可诱导细胞凋亡，逆转耐药。在本研究中，我们探索了miR-21抑制剂(miR-21i)和替莫唑胺(TMZ)联合治疗人脑胶质瘤细胞的最有效方案。3种肿瘤细胞系，U251磷酸酶和紧张素同源物(PTEN)突变体，LN229(PTEN野生型)和U87(PTEN功能丧失)，在体外评价了设计的治疗(先给miR-21i 4/8h，然后再用TMZ，先给药4/8h，然后再用miR-21i，或联合用药)的抗肿瘤作用。预先给药4h后，U251和U87细胞才表现出协同抗增殖和促凋亡作用，而LN229细胞在联合用药时抗肿瘤效果最佳。我们的数据表明，给药的顺序和时机的影响取决于细胞系的PTEN状态。在PTEN功能丧失的细胞中，最大限度地抑制STAT3和磷酸化的STAT3的抑制效果最好。我们的结果表明，在胶质瘤联合治疗中，给药的顺序和时机都是至关重要的。
Down-regulation of microRNA-21 (miR-21) can induce cell apoptosis and reverse drug resistance in cancer treatments. In this study, we explored the most effective schedule of the miR-21 inhibitor (miR-21i) and Temozolomide (TMZ) combined treatment in human glioma cells. Three tumor cell lines, U251 phosphatase and tensin homologue (PTEN) mutant, LN229 (PTEN wild-type), and U87 (PTEN loss of function), were subjected to evaluate the antitumor effects of deigned treatments (a predose of miR-21i for 4/8 h and then a subsequent TMZ treatment, a predose of TMZ for 4/8 h and then a subsequent miR-21i treatment, or a concomitant treatment) in vitro. A synergistic antiproliferative and proapoptotic activity was only obtained in U251 and U87 cells when a predose was administered for 4 h before the treatment of the other therapeutic agent, while the best antitumor effect in LN229 cells was achieved by using the concomitant treatment. Our data indicate that the effect of sequence and timing of administration is dependent on the PTEN status of cell lines. The best suppression effect was achieved by a maximal inhibition of STAT3 and phosphorylated STAT3, in PTEN loss of function cells. Our results reveal that both the sequence and the timing of administration are crucial in glioma combination therapy.