title: The combination of MLN2238 (ixazomib) with interferon-alpha results in enhanced cell death in melanoma.
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.
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.
authors: Lorena P
authors: LP
authors: Suarez-Kelly
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.
authors: Gregory M
authors: GM
authors: Kemper
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.|Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA.
authors: Megan C
authors: MC
authors: Duggan
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.|Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA.
authors: Andrew
authors: A
authors: Stiff
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.
authors: Tiffany C
authors: TC
authors: Noel
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.|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.
authors: Joseph
authors: J
authors: Markowitz
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.|Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus OH, USA.
authors: Eric A
authors: EA
authors: Luedke
authors: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
authors: Vedat O
authors: VO
authors: Yildiz
authors: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
authors: Lianbo
authors: L
authors: Yu
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.
authors: Alena Cristina
authors: AC
authors: Jaime-Ramirez
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.
authors: Volodymyr
authors: V
authors: Karpa
authors: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
authors: Xiaoli
authors: X
authors: Zhang
authors: The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.|Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus OH, USA.
authors: William E
authors: WE
authors: Carson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001896:Boron Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D001896:Boron Compounds; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D061988:Proteasome Inhibitors; D011994:Recombinant Proteins; C548400:ixazomib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D046988:Proteasome Endopeptidase Complex; D005998:Glycine
keywords: MLN2238; interferon-alpha; ixazomib; melanoma; proteasome inhibitor