School of Materials Science & Engineering, Tianjin University, Tianjin 300072, China.
Mol Pharm. 2012 Sep 4;9(9):2636-45. doi: 10.1021/mp3002039. Epub 2012 Aug 23.
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.
下调 microRNA-21（miR-21）可以诱导细胞凋亡并逆转癌症治疗中的耐药性。在这项研究中，我们探讨了 miR-21 抑制剂（miR-21i）和替莫唑胺（TMZ）联合治疗人胶质瘤细胞的最有效方案。将三种肿瘤细胞系 U251 磷酸酶和张力蛋白同源物（PTEN）突变体、LN229（PTEN 野生型）和 U87（PTEN 功能丧失）进行处理，以评估设计的治疗方案（miR-21i 预给药 4/8 h 然后进行 TMZ 治疗、TMZ 预给药 4/8 h 然后进行 miR-21i 治疗或同时治疗）的体外抗肿瘤作用。只有在 U251 和 U87 细胞中，在给予另一种治疗药物前预给药 4 h 时，才会获得协同的抗增殖和促凋亡活性，而在 LN229 细胞中，最佳的抗肿瘤效果是通过同时治疗获得的。我们的数据表明，给药顺序和时间的效果取决于细胞系的 PTEN 状态。在 PTEN 功能丧失的细胞中，通过最大程度地抑制 STAT3 和磷酸化 STAT3 ，可以达到最佳的抑制效果。我们的结果表明，在胶质细胞瘤联合治疗中，给药的顺序和时间都非常重要。
