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Reduction of Myeloid‐Derived Suppressor Cells and Lymphoma Growth by a Natural Triterpenoid
Author(s) -
Radwan Faisal F.Y.,
Hossain Azim,
God Jason M.,
Leaphart Nathan,
Elvington Michelle,
Nagarkatti Mitzi,
Tomlinson Stephen,
Haque Azizul
Publication year - 2015
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.24946
Subject(s) - cancer research , lymphoma , cd8 , cytotoxic t cell , apoptosis , biology , immune system , in vivo , t cell , immunology , in vitro , biochemistry , microbiology and biotechnology
Abstract Lymphoma is a potentially life threatening disease. The goal of this study was to investigate the therapeutic potential of a natural triterpenoid, Ganoderic acid A (GA‐A) in controlling lymphoma growth both in vitro and in vivo. Here, we show that GA‐A treatment induces caspase‐dependent apoptotic cell death characterized by a dose‐dependent increase in active caspases 9 and 3, up‐regulation of pro‐apoptotic BIM and BAX proteins, and a subsequent loss of mitochondrial membrane potential with release of cytochrome c. In addition to GA‐A's anti‐growth activity, we show that lower doses of GA‐A enhance HLA class II‐mediated antigen (Ag) presentation and CD4+ T cell recognition of lymphoma cells in vitro. The therapeutic relevance of GA‐A treatment was also tested in vivo using the EL4 syngeneic mouse model of metastatic lymphoma. GA‐A‐treatment significantly prolonged survival of EL4 challenged mice and decreased tumor metastasis to the liver, an outcome accompanied by a marked down‐regulation of STAT3 phosphorylation, reduction myeloid‐derived suppressor cells (MDSCs), and enhancement of cytotoxic CD8+ T cells in the host. Thus, GA‐A not only selectively induces apoptosis in lymphoma cells, but also enhances cell‐mediated immune responses by attenuating MDSCs, and elevating Ag presentation and T cell recognition. The demonstrated therapeutic benefit indicates that GA‐A is a candidate for future drug design for the treatment of lymphoma. J. Cell. Biochem. 116: 102–114, 2015. © 2014 Wiley Periodicals, Inc.