Anti‐miR‐21 oligonucleotide sensitizes leukemic K562 cells to arsenic trioxide by inducing apoptosis

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.

(Cancer Sci 2010; 101: 948–954)