Department of Biochemistry, Medical College of Jinan University, Guangzhou, China.
Cancer Sci. 2010 Apr;101(4):948-54. doi: 10.1111/j.1349-7006.2010.01489.x. Epub 2010 Jan 7.
Arsenic trioxide (ATO), an ancient traditional Chinese medicine, has been successfully used as a therapeutic agent for leukemia. Drug resistance and toxicity are major concerns with the treatment. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that might modulate cellular sensitivity to anticancer drugs. miRNA-21 (miR-21) is one of the most prominent miRNAs involved in various aspects of human cancers. However, miR-21 has been rarely characterized in chronic myelogenous leukemia (CML). Here, we used a specific anti-miR-21 oligonucleotide (AMO-miR-21) to sensitize K562 cells to ATO by degradation of miR-21. The results showed that both AMO-miR-21 and ATO caused growth inhibition, apoptosis, and G1-phase arrest in K562 cells. Meanwhile, AMO-miR-21 significantly promoted ATO-mediated growth inhibition and apotosis without affecting the G1 phase. Apoptotic cells were confirmed morphologically with Giemsa's staining. Furthermore, dual-luciferase reporter vector, containing two tandem miR-21 binding sites from PDCD4 3'UTR, validated that PDCD4 was directly regulated by miR-21. Therefore, AMO-miR-21 sensitized leukemic K562 cells to ATO by inducing apoptosis partially due to its up-regulation of PDCD4 protein level. The combination of ATO and AMO-miR-21 present therapeutic potential for CML.
三氧化二砷（ATO），一种古老的中药，已成功用作白血病的治疗剂。耐药性和毒性是治疗的主要关注点。microRNAs（miRNAs）是内源性的小非编码 RNA 分子，可能调节细胞对抗癌药物的敏感性。miR-21（miR-21）是涉及人类癌症各个方面的最突出的 miRNA 之一。然而，miR-21 在慢性髓性白血病（CML）中很少被描述。在这里，我们使用了一种特异性抗 miR-21 寡核苷酸（AMO-miR-21）通过降解 miR-21 来使 K562 细胞对 ATO 敏感。结果表明，AMO-miR-21 和 ATO 均引起 K562 细胞生长抑制、凋亡和 G1 期阻滞。同时，AMO-miR-21 显著促进 ATO 介导的生长抑制和凋亡，而不影响 G1 期。通过 Giemsa 染色可形态学确认凋亡细胞。此外，包含 PDCD4 3'UTR 中两个串联 miR-21 结合位点的双荧光素酶报告载体验证了 PDCD4 被 miR-21 直接调控。因此，AMO-miR-21 通过诱导部分凋亡使白血病 K562 细胞对 ATO 敏感，这部分归因于其对 PDCD4 蛋白水平的上调。ATO 和 AMO-miR-21 的联合为 CML 提供了治疗潜力。
