Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: a combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors
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Joanna Kopecka1, Stefania Porto2, Sara Lusa3, Elena Gazzano1, Giuseppina Salzano4, Martha Leonor Pinzòn-Daza1,5, Antonio Giordano6, Vincenzo Desiderio7, Dario Ghigo1, Giuseppe De Rosa3, Michele Caraglia2,6, Chiara Riganti1
1Department of Oncology, University of Turin, Turin, 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
5Universidad del Rosario, Facultad de Ciencias Naturales y Matemáticas, RG in Biochemistry and Biotechnology (BIO-BIO), Bogotá, Colombia
6Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
7Department of Experimental Medicine, Second University of Naples, Naples, Italy
Michele Caraglia, e-mail: [email protected]
Chiara Riganti, e-mail: [email protected]
Keywords: self-assembling nanoparticles, zoledronic acid, doxorubicin resistance, immunoresistance, immunosuppression
Received: September 24, 2015 Accepted: February 16, 2016 Published: March 09, 2016
The resistance to chemotherapy and the tumor escape from host immunosurveillance are the main causes of the failure of anthracycline-based regimens in breast cancer, where an effective chemo-immunosensitizing strategy is lacking.
The clinically used aminobisphosphonate zoledronic acid (ZA) reverses chemoresistance and immunoresistance in vitro. Previously we developed a nanoparticle-based zoledronic acid-containing formulation (NZ) that allowed a higher intratumor delivery of the drug compared with free ZA in vivo. We tested its efficacy in combination with doxorubicin in breast tumors refractory to chemotherapy and immune system recognition as a new combinatorial approach to produce chemo- and immunosensitization.
NZ reduced the IC50 of doxorubicin in human and murine chemoresistant breast cancer cells and restored the doxorubicin efficacy against chemo-immunoresistant tumors implanted in immunocompetent mice. By reducing the metabolic flux through the mevalonate pathway, NZ lowered the activity of Ras/ERK1/2/HIF-1α axis and the expression of P-glycoprotein, decreased the glycolysis and the mitochondrial respiratory chain, induced a cytochrome c/caspase 9/caspase 3-dependent apoptosis, thus restoring the direct cytotoxic effects of doxorubicin on tumor cell. Moreover, NZ restored the doxorubicin-induced immunogenic cell death and reversed the tumor-induced immunosuppression due to the production of kynurenine, by inhibiting the STAT3/indoleamine 2,3 dioxygenase axis. These events increased the number of dendritic cells and decreased the number of immunosuppressive T-regulatory cells infiltrating the tumors.
Our work proposes the use of nanoparticle encapsulating zoledronic acid as an effective tool overcoming at the same time chemoresistance and immunoresistance in breast tumors, thanks to the effects exerted on tumor cell and tumor-infiltrating immune cells.
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