Epigenetics targeted protein-vorinostat nanomedicine inducing apoptosis in heterogeneous population of primary acute myeloid leukemia cells including refractory and relapsed cases.

Abstract

Aberrant epigenetics play a key role in the onset and progression of acute myeloid leukemia (AML). Herein we report in silico modelling based development of a novel, protein-vorinostat nanomedicine exhibiting selective and superior anti-leukemic activity against heterogeneous population of AML patient samples (n=9), including refractory and relapsed cases, and three representative cell lines expressing CD34(+)/CD38(-) stem cell phenotype (KG-1a), promyelocytic phenotype (HL-60) and FLT3-ITD mutation (MV4-11). Nano-vorinostat having ~100nm size exhibited enhanced cellular uptake rendering significantly lower IC50 in AML cell lines and patient samples, and induced enhanced HDAC inhibition, oxidative injury, cell cycle arrest and apoptosis compared to free vorinostat. Most importantly, nanomedicine showed exceptional single-agent activity against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. Collectively, this epigenetics targeted nanomedicine appears to be a promising therapeutic strategy against various French-American-British (FAB) classes of AML.

FROM THE CLINICAL EDITOR:

Through the use of a protein-vorinostat agent, exceptional single-agent activity was demonstrated against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. The studied epigenetics targeted nanomedicine approach is a promising therapeutic strategy against various French-American-British classes of acute myeloid leukemia.

• Authors: Parwathy Chandran, Anu Kavalakatt, Giridharan Loghanathan Malarvizhi, Divya Rani Vikraman Nair Vasanthakumari, Archana Payickattu Retnakumari, Neeraj Sidharthan, Keechilat Pavithran, Shantikumar Nair, Manzoor Koyakutty
• Journal: Nanomedicine : nanotechnology, biology, and medicine (Nanomedicine) Vol. 10 Issue 4 Pg. 721-32 (May 2014) ISSN: 1549-9642 [Electronic] United States
• PMID: 24103301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Vorinostat

Topics

• Apoptosis (drug effects)
• Computer Simulation
• Epigenesis, Genetic (drug effects)
• HL-60 Cells
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (pharmacology)
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism, pathology)
• Models, Biological
• Nanomedicine (methods)
• Vorinostat