Proteasome inhibitor clioquinol as a candidate drug in prophylaxis and treatment of acute graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) is one of the most severe complications after allogeneic bone marrow transplantation. It exhibits a complex pathophysiology resulting from donor T cell recognition of a genetically disparate recipient that is unable to reject the donor cells following allogeneic hematopoietic stem-cell transplantation (HSCT) and ultimately causes multiple organs destruction. Currently practiced prophylaxis of GVHD includes T-cell depletion (TCD) and/or immunosuppressive medication. However, immunosuppressive agents may have serious side effects and selective removal of T cells from the graft significantly reduces the beneficial effects of donor T cells, especially anti-tumor activity. These deleterious side effects of infectious complications and relapse of underlying malignancy remain barriers to successful approaches. The proteasomal pathway of protein degradation plays a key role in different key cell functions such as cell cycle regulation, apoptosis and costimulation. Proteasome inhibition in cancer cells leads to induction of tumor cell death and also plays critical roles in T cell activation, proliferation, and apoptosis, in part, because of blockade of NF-κB activation. Recently it was reported clioquinol can inhibit the proteasomal chymotrypsin-like activity and induce apoptotic cell death in leukemia and myeloma. We hypothesized that proteasome inhibitor clioquinol could be a candidate drug for pharmacological prophylaxis and treatment of GVHD with retention of graft-versus-tumor (GVT) effect.