Abstract
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.
Highlights
P-gp which can efficiently inhibit the proliferation of MCF-7ADR cells[12]
To dissect the underlying molecular rules, we developed a model of leukemia resistance to DOX by treating K562 cells with increasing doses of DOX for > 2 months to select DOX-resistant cells (K562DR)
To investigate whether the NCL/ miR-221/DNMT1 pathway was involved in the multidrug-resistant phenotype of leukemic cells, we performed Quantitative PCR (qPCR) and Western blot assays to measure NCL and DNMT1 RNA or protein levels in K562DR cells
Summary
Rong Deng[1,2], Bai Ji3, Hongliang Yu2, Wei Bao[1], Zhuoqi Yang[2], Ying Yu1, Yahan Cui[2], Yangyang Du1, Meiyu Song[1], Shujun Liu[4], Kamel Meguellati2 & FeiYan 1,2. 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. Leukemia is a heterogeneous form of cancer characterized by the abnormal growth of leukocytes due to genetic aberrations and mutations Chemotherapeutic agents such as doxorubicin are frequently used as the first-line therapy for patients with leukemia, but the effectiveness of these agents is limited by drug resistance[1]. A key mechanism associated with MDR is the chemotherapeutic agent- induced overexpression of P-glycoprotein (P-gp), a plasma membrane drug efflux pump that possesses high anticancer agent transport efficiency, leading to a reduction in complete remission rates during cancer therapy. Inhibition of P-gp expression or its drug efflux function has been an important strategy to overcome MDR8,9
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