Sustained targeting of Bcr-Abl + leukemia cells by synergistic action of dual drug loaded nanoparticles and its implication for leukemia therapy.

Abstract

Chimeric Bcr-Abl oncoprotein is the molecular hallmark of chronic myeloid leukemia (CML) and hence a lucrative target for therapeutic intervention of CML.However, limited efficacy of current first line treatment for CML calls attention for further development of more efficient strategies. Recently, much attention has been given to nanoparticle (NP) based drug delivery systems loaded with dual drugs to improve current disease therapies by overcoming toxicity and other side effects associated with high doses of single drugs. In the present study, we document to explore an approach to simultaneously deliver two drugs at target sites (i.e. Bcr-Abl oncoprotein) using poly (lactide-co-glycolide) (PLGA) nanoparticles. Preliminary study included screening six different anticancer drugs and their nanoformulations on leukemia cells. Results confirmed superlative antileukemic activity of paclitaxel (especially in formulations) on model cell line K562, but only upon longer exposure. Thus to lower time of action of such a potent drug, different drug combination were experimented taking the advantage of synergistic action of both the drugs. Evaluation at molecular and genetic level helped to identify signaling pathways upstream and downstream of Bcr-Abl, leading to its suppression. Results helped to illustrate dynamic changes primarily involved in inducing apoptotic activities on drug exposure of leukemia cells, thereby facilitating us to integrate different drug combinations in a more specific manner in near future to study CML in clinical settings.

• Authors: Sarbari Acharya, Sanjeeb K Sahoo
• Journal: Biomaterials (Biomaterials) Vol. 32 Issue 24 Pg. 5643-62 (Aug 2011) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 21600647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Polylactic Acid-Polyglycolic Acid Copolymer
• Polyglycolic Acid
• Lactic Acid
• Curcumin
• Paclitaxel
• Sirolimus

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Curcumin (pharmacology)
• Drug Synergism
• Humans
• Lactic Acid (chemistry)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Nanoparticles (chemistry)
• Paclitaxel (pharmacology)
• Polyglycolic Acid (chemistry)
• Polylactic Acid-Polyglycolic Acid Copolymer
• Polymerase Chain Reaction
• Sirolimus (pharmacology)