Inhibition of TBK1 and IKKε by Amlexanox Synergizes with Bortezomib to Reduce Myeloma Cell Growth

School Name

Home School

Grade Level

12th Grade

Presentation Topic

Biochemistry

Presentation Type

Mentored

Mentor

Mentor: Deborah Galson and Quanhong Sun, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute

Oral Presentation Award

2nd Place

Written Paper Award

3rd Place

Abstract

Multiple myeloma causes increased osteoclast activity and decreased osteoblast formation that results in extensive bone damage. The aim of this study was to explore the potential usefulness of Amlexanox, a TBK1 and IKKε kinase inhibitor that decreases osteoclastogenesis, as a potential therapeutic for MM bone disease. Amlexanox alone slowed the growth of myeloma cell lines. Therefore, this study tested the effects of combining Amlexanox with a current myeloma therapeutic, the protease inhibitor Bortezomib, on myeloma cell growth and apoptosis. First, the effects of a single suboptimal dose of Amlexanox and Bortezomib alone and in combination on five MM cell lines were assessed using CellTiter-Glo assays. This was followed by analyses of a set of total drug concentrations (¼, ½, 1, 2, 4-fold) that maintained a constant ratio of Amlexanox to Bortezomib based on their IC50s to determine whether their combined effect on the myeloma cells was antagonistic, additive, or synergistic. The results of the assay showed that the drugs combined antagonistically at low doses and synergistically from the IC50 up. In addition, the effects of Amlexanox on different stages of bone marrow differentiation to osteoclasts were tested using a TRAP assay. These results showed that the first 48 hours after exposure were the most critical to decrease osteoclast formation. The results of this study suggest that Amlexanox combined with Bortezomib is a potential therapeutic treatment for myeloma patients and the Amlexanox may help to prevent excess osteoclastogenesis in myeloma patients.

Location

Wall 118

Start Date

3-25-2017 10:00 AM

Presentation Format

Oral and Written

Group Project

No

COinS
 
Mar 25th, 10:00 AM

Inhibition of TBK1 and IKKε by Amlexanox Synergizes with Bortezomib to Reduce Myeloma Cell Growth

Wall 118

Multiple myeloma causes increased osteoclast activity and decreased osteoblast formation that results in extensive bone damage. The aim of this study was to explore the potential usefulness of Amlexanox, a TBK1 and IKKε kinase inhibitor that decreases osteoclastogenesis, as a potential therapeutic for MM bone disease. Amlexanox alone slowed the growth of myeloma cell lines. Therefore, this study tested the effects of combining Amlexanox with a current myeloma therapeutic, the protease inhibitor Bortezomib, on myeloma cell growth and apoptosis. First, the effects of a single suboptimal dose of Amlexanox and Bortezomib alone and in combination on five MM cell lines were assessed using CellTiter-Glo assays. This was followed by analyses of a set of total drug concentrations (¼, ½, 1, 2, 4-fold) that maintained a constant ratio of Amlexanox to Bortezomib based on their IC50s to determine whether their combined effect on the myeloma cells was antagonistic, additive, or synergistic. The results of the assay showed that the drugs combined antagonistically at low doses and synergistically from the IC50 up. In addition, the effects of Amlexanox on different stages of bone marrow differentiation to osteoclasts were tested using a TRAP assay. These results showed that the first 48 hours after exposure were the most critical to decrease osteoclast formation. The results of this study suggest that Amlexanox combined with Bortezomib is a potential therapeutic treatment for myeloma patients and the Amlexanox may help to prevent excess osteoclastogenesis in myeloma patients.