Synergy of Interferons and Bortezomib: Advantages of Combination Treatments in Facilitating Apoptosis in Multiple Myeloma Cells

Abstract:

Interferon alpha (IFN-α) and the proteasome inhibitor bortezomib are both clinically indicated for the treatment of specific hematological cancers. Interferons function by controlling the expression of hundreds of genes in multiple pathways. Bortezomib is a reversible 26S proteasome inhibitor that affects multiple signaling pathways selectively in tumor cells and has demonstrated low toxicity in patients. Combination therapy in oncology is a widely practiced treatment methodology that can lead to improved clinical outcomes. We have determined the individual antiproliferative (AP) activities of bortezomib, Type I IFNs (α, β, ω) and Type II IFN (IFN-γ) in the U266 human multiple myeloma cell line by colorimetric and luminescent cell viability assays. The individual effectiveness of each treatment varied in a concentration and time-dependent manner. The IC50 for bortezomib at day 1 (6.8 nM) dropped to 2.3 nM at day 6. The IC50 for Type I IFNs were ng/ml level at day 2 and decreased to pg/ml level at day 6. Combination of each IFN and bortezomib further decreased the IC50 of treatment AP effects. Cell cycle analysis by propidium iodide (PI) staining flow cytometry revealed increased hypodiploid population in the combination treatment. Functional studies revealed a synergy of growth inhibition due to increased apoptosis (Annexin V/PI staining) and caspase 3/7 activation. Overall, Type I IFNs (α, β, ω) displayed greater synergy indices (CI 0.3-0.5) than IFN-γ (CI 0.6-0.7) in both growth inhibitory and apoptotic assays.

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