Self-assembling nanoparticles encapsulating zoledronic acid revert multidrug resistance in cancer cells.

Abstract

The overexpression of ATP binding cassette (ABC) transporters makes tumor cells simultaneously resistant to several cytotoxic drugs. Impairing the energy metabolism of multidrug resistant (MDR) cells is a promising chemosensitizing strategy, but many metabolic modifiers are too toxic in vivo. We previously observed that the aminobisphosphonate zoledronic acid inhibits the activity of hypoxia inducible factor-1a (HIF-1a), a master regulator of cancer cell metabolism. Free zoledronic acid, however, reaches low intratumor concentration. We synthesized nanoparticle formulations of the aminobisphosphonate that allow a higher intratumor delivery of the drug. We investigated whether they are effective metabolic modifiers and chemosensitizing agents against human MDR cancer cells in vitro and in vivo. At not toxic dosage, nanoparticles carrying zoledronic acid chemosensitized MDR cells to a broad spectrum of cytotoxic drugs, independently of the type of ABC transporters expressed. The nanoparticles inhibited the isoprenoid synthesis and the Ras/ERK1/2-driven activation of HIF-1α, decreased the transcription and activity of glycolytic enzymes, the glucose flux through the glycolysis and tricarboxylic acid cycle, the electron flux through the mitochondrial respiratory chain, the synthesis of ATP. So doing, they lowered the ATP-dependent activity of ABC transporters, increasing the chemotherapy efficacy in vitro and in vivo. These effects were more pronounced in MDR cells than in chemosensitive ones and were due to the inhibition of farnesyl pyrophosphate synthase (FPPS), as demonstrated in FPPS-silenced tumors. Our work proposes nanoparticle formulations of zoledronic acid as the first not toxic metabolic modifiers, effective against MDR tumors.

• Authors: Joanna Kopecka, Stefania Porto, Sara Lusa, Elena Gazzano, Giuseppina Salzano, Antonio Giordano, Vincenzo Desiderio, Dario Ghigo, Michele Caraglia, Giuseppe De Rosa, Chiara Riganti
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 31 Pg. 31461-78 (Oct 13 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26372812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Bone Density Conservation Agents
• Diphosphonates
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Imidazoles
• Zoledronic Acid

Topics

• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Bone Density Conservation Agents (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Diphosphonates (therapeutic use)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Imidazoles (therapeutic use)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nanoparticles (administration & dosage, chemistry)
• Oxidative Stress (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Zoledronic Acid