Work

The combination of MLN2238 (ixazomib) with interferon-alpha results in enhanced cell death in melanoma

Year: 2016

Type: article

Abstract: // Lorena P. Suarez-Kelly 1, * , Gregory M. Kemper 1, * , Megan C. Duggan 1, 2 , Andrew Stiff 1, 2 , Tiffany C. Noel 1 , Joseph Markowitz 1, 3 , Eric A. Luedke 1, 4 , Vedat O. Yildiz 5 , Lianbo Yu 5 , Alena Cristina Jaime-Ramirez 1 , Volodymyr Karpa 1 , Xiaoli Zhang 5 , William E. Carson III 1, 4 1 The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA 2 Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA 3 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus OH, USA 4 Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus OH, USA 5 Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA * These authors have contributed equally to this work Correspondence to: William E. Carson III, email: [email protected] Keywords: MLN2238, ixazomib, melanoma, proteasome inhibitor, interferon-alpha Received: December 23, 2015 Accepted: October 10, 2016 Published: October 21, 2016 ABSTRACT The ubiquitin-proteasome signaling pathway is critical for cell cycle regulation and neoplastic growth. Proteasome inhibition can activate apoptotic pathways. Bortezomib, a selective proteasome inhibitor, has anti-melanoma activity. MLN2238 (ixazomib), an oral proteasome inhibitor, has improved pharmacotherapeutic parameters compared to bortezomib. Interferon-alpha (IFN-α), an immune boosting agent, is FDA-approved for treatment of melanoma. In this study in vitro and in vivo evaluation of the antitumor potential of ixazomib and combination treatments with ixazomib and IFN-α were performed. Apoptosis induced by ixazomib was first observed at 12 hours and was maximal at 48 hours with similar levels of cell death compared to bortezomib. IFN-α alone had little effect on cell viability in vitro . However, the combination of ixazomib with IFN-α significantly enhanced ixazomib’s ability to induce apoptotic cell death in BRAF V600E mutant and BRAF wild-type human melanoma tumor cells. The combination of ixazomib and IFN-α also enhanced inhibition of cell proliferation in BRAF V600E mutant melanoma tumor cells; however, this was not seen in BRAF wild-type cells. Ixazomib-induced apoptosis was associated with processing of the pro-apoptotic proteins procaspase-3, -7, -8, and -9, and cleavage of poly-ADP-ribose polymerase (PARP). In an in vivo xenograft model of human melanoma, combination treatment with IFN-α-2b and ixazomib demonstrated a significant reduction in tumor volume when compared to vehicle (p = 0.005) and single therapy ixazomib (p = 0.017) and IFN-α-2b (p = 0.036). These pre-clinical results support further evaluation of combination treatment with ixazomib and IFN-α for the treatment of advanced BRAF V600E mutant melanoma.

Source: Oncotarget

DOI: 10.18632/oncotarget.12791