Modulating the Growth and Imatinib Sensitivity of Chronic Myeloid Leukemia Stem/Progenitor Cells with Pullulan/MicroRNA Nanoparticles In Vitro

J Biomed Nanotechnol. 2015 Nov;11(11):1961-74. doi: 10.1166/jbn.2015.2147.

Abstract

Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring Philadelphia chromosome (Ph) to generate BCR-ABL fusion gene whose protein product has deregulated tyrosine kinase activity. Specific inhibitors against BCR-ABL, such as Imatinib mesylate (IM), have greatly improved CML management; however, no single agent is a cure yet. Delivery of microRNA (miRNA) using non-viral vectors has been utilized to inhibit various cancer cells; however, the efficacy of this approach to target CML stem/progenitor cells has not been elucidated. In this study, we firstly validated that spermine-introduced pullulan (Ps) was a robust non-viral vector for delivery of miRNA to CML cells, including the CD34+ cells from clinical isolates. We then found that the miR-181a/RALA (V-ral simian leukemia viral oncogene homolog A) axis was aberrantly expressed in the CML CD34+ cells. The delivery of miR-181a specifically inhibited the growth of CML CD34+ cells, possibly via the inhibition of RALA. In contrast, miR-181a did not evidently affect the normal hematopoietic CD34+ cells. In addition, miR-181a increased IM sensitivity of the CD34+ CML cells. Taken together, we have therefore demonstrated that the delivery of miR-181a using Ps to CML stem/progenitor cells leads to their growth inhibition and enhancement of IM sensitivity, which will possibly be beneficial to CML treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Glucans / chemistry
  • Humans
  • Imatinib Mesylate / chemistry
  • Imatinib Mesylate / pharmacokinetics
  • Imatinib Mesylate / pharmacology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Male
  • MicroRNAs / chemistry
  • MicroRNAs / genetics
  • MicroRNAs / pharmacokinetics
  • MicroRNAs / pharmacology*
  • Middle Aged
  • Nanomedicine
  • Nanoparticles / chemistry*
  • Neoplastic Stem Cells / drug effects*
  • Transfection
  • Young Adult

Substances

  • Antineoplastic Agents
  • Glucans
  • MIrn181 microRNA, human
  • MicroRNAs
  • Imatinib Mesylate
  • pullulan