Self-assembling nanoparticles encapsulating zoledronic acid revert multidrug resistance in cancer cells
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Joanna Kopecka1,*, Stefania Porto2,*, Sara Lusa3,*, Elena Gazzano1, Giuseppina Salzano4, Antonio Giordano5,6, Vincenzo Desiderio7, Dario Ghigo1, Michele Caraglia2,5, Giuseppe De Rosa3, Chiara Riganti1
1Department of Oncology, University of Torino, Torino, Italy
2Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
3Department of Pharmacy, Federico II University of Naples, Naples, Italy
4Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA
5Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
6Department of Medicine, Surgery and Neuroscience University of Siena, Italy
7Department of Experimental Medicine, Second University of Naples, Naples, Italy
*These authors have contributed equally to this work
Michele Caraglia, e-mail: [email protected]
Chiara Riganti, e-mail: [email protected]
Keywords: self-assembling nanoparticles, zoledronic acid, ATP binding cassette transporters, multidrug resistance, hypoxia inducible factor-1α
Received: July 07, 2015 Accepted: August 27, 2015 Published: September 09, 2015
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.
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