Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

// Iris Chiara Salaroglio 1, * , Ivana Campia 1, * , Joanna Kopecka 1 , Elena Gazzano 1 , Sara Orecchia 2 , Dario Ghigo 1 , Chiara Riganti 1 1 Department of Oncology, University of Torino, Italy 2 S.C. Anatomia Patologica, Azienda Ospedaliera S.S. Antonio e Biagio, Alessandria, Italy * These authors have contributed equally to this work Correspondence to: Dario Ghigo, e-mail: dario.ghigo@unito.it Keywords: malignant mesothelioma, chemoresistance, immunosuppression, indoleamine 1,2 dioxygenase, zoledronic acid Received: August 28, 2014 Accepted: November 11, 2014 Published: December 31, 2014 ABSTRACT The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells.