Researchers uncover new mechanism in multiple myeloma cells
Researchers at Virginia Commonwealth University Massey Cancer Center have discovered a mechanism in multiple myeloma cells that plays a critical role in the cells’ ability to resist treatments involving a class of drugs known as histone deacetylase inhibitors (HDACIs). The findings could lead to more effective treatments for multiple myeloma, leukemia and other malignant blood disorders.
Reported in the Journal of Biological Chemistry, research from the laboratory of Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center, showed that blocking activation of a protein complex known as NF-kappaB (NF-kB) significantly increases the ability of HDACIs to induce cell death in multiple myeloma cells. NF-kB plays a major role in controlling the transcription of DNA, the first in a series of processes that determine genetic expression. By blocking NF-kB, multiple myeloma cells are unable to activate a cytoprotective response to DNA damage caused by HDACIs.
In this study, Grant’s team used a drug known as an IKK inhibitor to block NF-kB activation, which caused multiple myeloma cells to die when exposed to HDACIs to an extent that was substantially greater than when the cells were treated with HDACIs alone. The IkB Kinase (IKK) is an enzyme responsible for activating NF-kB through a process known as phosphorylation.
“Our research elucidates the mechanisms by which IKK inhibitors act to block NF-kB function,” says Grant. “Previous studies focused primarily on the ability of IKK inhibitors to block NF-kB entry into the cell’s nucleus. Our study demonstrated that IKK inhibitors also block phosphorylation of NF-kB on a particular site, thus amplifying inhibition of this cytoprotective pathway and lowering the threshold for HDACI-mediated cell death in malignant cells.”
For nearly a decade, Grant’s laboratory has been exploring the mechanisms by which the anti-cancer effects of HDACIs might be improved, focusing on NF-kB and other pathways. His team plans to continue investigating different IKK inhibitors to improve the activity of HDACIs against various blood cancers.
“We hope that in the years to come these studies will provide a foundation for implementing multiple clinical trials testing combinations of IKK and HDAC inhibitors for the treatment of multiple myeloma, leukemia and other malignant blood disorders,” says Grant.
The full research manuscript is available online at: http://www.jbc.org/content/286/39/34036.
The lead author on the study was Yun Dai, M.D., Ph.D., associate professor in the Department of Internal Medicine at VCU School of Medicine. Grant also collaborated with Paul Dent, Ph.D., Universal Corporation Distinguished Professor for Cancer Cell Signaling at VCU Massey and professor and vice chair of research in the Department of Neurosurgery at the VCU School of Medicine, and Shuang Chen, M.D., Li Wang, Xinyan Pei, M.D., Vanessa Funk and Lora Kramer, all from the Department of Internal Medicine at VCU School of Medicine.