Oncotarget

Research Papers:

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

Lorena P. Suarez-Kelly, Gregory M. Kemper, Megan C. Duggan, Andrew Stiff, Tiffany C. Noel, Joseph Markowitz, Eric A. Luedke, Vedat O. Yildiz, Lianbo Yu, Alena Cristina Jaime-Ramirez, Volodymyr Karpa, Xiaoli Zhang and William E. Carson III _

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Oncotarget. 2016; 7:81172-81186. https://doi.org/10.18632/oncotarget.12791

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Abstract

Lorena P. Suarez-Kelly1,*, Gregory M. Kemper1,*, Megan C. Duggan1,2, Andrew Stiff1,2, Tiffany C. Noel1, Joseph Markowitz1,3, Eric A. Luedke1,4, Vedat O. Yildiz5, Lianbo Yu5, Alena Cristina Jaime-Ramirez1, Volodymyr Karpa1, Xiaoli Zhang5, William E. Carson III1,4

1The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA

2Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA

3Division 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

4Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus OH, USA

5Center 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.


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