Resistance to chemotherapy and molecularly targeted therapies is a major problem in current leukemia treatments. Here, we investigated cross-talk between the miR-221 network and P-glycoprotein (P-gp) in doxorubicin-induced drug resistance of leukemia cells. Multifunctional gold nanoparticles were designed and synthesized to co-deliver three anticancer agents, AS1411, doxorubicin and anti-221, for improving leukemia treatment efficacy. These nanoparticles significantly inhibited the proliferation and clonogenic potential, and induced apoptosis of drug-resistant leukemia cells. The decreased growth of drug-resistant cells induced by these nanoparticles was associated with marked downregulation of miR-221 and DNMT1, leading to restored p27kip1 and p15ink4b tumor suppressor expression, as well as miR-221-mediated reduction of P-gp expression. Finally, primary blasts derived from leukemia patients experiencing chemoresistant relapse that were exposed to these nanoparticles were sensitized to doxorubicin, as evidenced by suppression of leukemic cell growth and a significant reduction of the doxorubicin IC50 value. Our findings provide proof of concept that this novel drug delivery system can precisely reverse the multidrug resistant leukemia phenotype based on preclinical models of leukemia, providing the framework for future clinical trials aimed at overcoming drug resistance and improving patient outcome.
Bibliographical noteFunding Information:
This work was supported by the National Natural Science Foundation of China (NSFC; projects 81870117, 81802805), the Jilin Province Science and Technology Development Plan (20190201252JC), the Startup Fund from Jilin University, China (451170102027, 451170102020, 1G317L321461), and the 8th Young Fund of the First Hospital of Jilin University (JDYY82017007).