DOI
https://doi.org/10.25772/WSKN-JT96
Defense Date
2009
Document Type
Thesis
Degree Name
Master of Science
Department
Biochemistry
First Advisor
Steven Grant
Abstract
Mechanisms underlying the interactions between the proteasome inhibitor carfilzomib and HDAC inhibitors were examined in both germinal center (GC) and activated B-cell (ABC) subtypes of human diffuse large B-cell lymphoma (DLBCL). Simultaneous exposure to minimally toxic concentrations of carfilzomib and HDAC inhibitor vorinostat resulted in the release of mitochondrial pro-apoptotic proteins SMAC and cytochrome c, pro-apoptotic caspase activation, and synergistic induction in apoptosis in both ABC and GC DLBCL subtypes. These events were associated with a marked increase in the stress kinase JNK, ROS generation, G2-M cell cycle arrest, as well as induction of DNA damage. Genetic knockdown of JNK resulted in a significant decrease in carfilzomib/vorinostat induced cell death. Co-administration of the antioxidant MnTBAP significantly reduced carfilzomib/vorinostat induced cell death, and resulted in a marked decrease in caspase-3 as well as a striking decrease in JNK phosphorylation. Tumor growth reduction was also observed in animal models that were treated with a combined regimen of carfilzomib and vorinostat. Finally, the combined treatment of carfilzomib/vorinostat was able to overcome any cross-resistance to carfIlzomib in bortezomib resistant cells. Collectively, these finding indicate that the combined regimen of carfilzomib and HDAC inhibitors promote lethality in ABC and GC human DLBCL cells by a variety of mechanisms both in vitro and in vivo. Further studies are necessary for clinical development of this drug regimen.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
May 2009