Download Antibody-induced nonapoptotic cell death in human lymphoma and

Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is
mediated through a novel reactive oxygen species-dependent pathway
Jamie Honeychurch, *Waleed Alduaij, Mahsa Azizyan, Eleanor J. Cheadle, Helene Pelicano, Andrei Ivanov, Peng Huang, Mark S.
Cragg, and Tim M. Illidge
BLOOD, 12 APRIL 2012 VOLUME 119, NUMBER 15
Presenter: Yu-Ling Cheng
Commentator: Dr. Nan-Shan Chang
Date/Time: Nov.8.2012 16:10-17:00
Location: Room 602, Med College Building
Background:
Monocolonal antibodies (mAbs) have revolutionized the treatment of B-cell malignancies. In particular,
mAbs direct to malignant B cell-surface antigens CD20 have proven the most clinically effective. Although
Fc-FcγR mechanisms are thought to account for much of mAb-induced tumor clearance, certain CD20 and
HLA-DR -specific mAbs potently evoke a nonapoptotic mode of cell death through an actin-dependent,
lysosomal-mediated process. However, the underlying mechanisms involved remain under-investigated.
Reactive oxygen species (ROS) are highly reactive molecules that regulate numerous essential cell
processes in living organisms. Although the production of ROS is closely associated with various apoptotic
stimuli, several studies have demonstrated that mAbs which trigger nonapoptotic cell death can stimulate
ROS generation and indicated that ROS play a vital role in executing various forms of nonapoptotic PCD.
Objective:
To investigate the role of reactive oxygen species in the monoclonal antibodies-induced nonapoptotic
cell death in B-cell malignancies.
Results:
Results of this paper showed that mAbs that potently induced cell death such as type II anti-CD20
mAbs (tositumomab and GA101) and anti-HLA DR mAbs (L243, 1D10 and WR18) produced high levels of
ROS in human B-lymphoma cell lines and primary B-cell chronic lymphocytic leukemia (B-CLL) cells. The
induction of both ROS and cell death were independent of the Fc domain. Interestingly, treatment of cells
with ROS scavengers abrogated mAb-induced PCD indicating that ROS are required for the execution of cell
death.
mAb-induced ROS generation occurred downstream of homotypic adhesion, reorganization of the actin
cytoskeleton, lysosome membrane permeabilization and the subsequent release of lysosomal cathepsins
into cytosol. mAb-induced ROS generation was independent of mitochondria and not inhibited by
antiapoptotic oncoprotein BCL-2 overexpression. Instead, ROS production and consequent cell death were
mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases activity.
Conclusion:
Their findings offer further insight into a previous unrecognized role for NADPH oxidase-derived ROS in
mediating mAb-induced nonapoptotic, lysosomal cell death pathway and provide a novel therapeutic
approach that may improve the clinical efficiency of mAbs.
References:
Alduaij W, Illidge TM. The future of anti-CD20 monoclonal antibodies: are we making progress? Blood. 2011;
117(11):2993-3001.