Reduction of myeloid-derived suppressor cells and lymphoma growth by a natural triterpenoid.

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.

• Authors: Faisal F Y Radwan, Azim Hossain, Jason M God, Nathan Leaphart, Michelle Elvington, Mitzi Nagarkatti, Stephen Tomlinson, Azizul Haque
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 116 Issue 1 Pg. 102-14 (Jan 2015) ISSN: 1097-4644 [Electronic] United States
• PMID: 25142864 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Triterpenes
• ganoderic acid

Topics

• Animals
• Cell Line, Tumor
• Cell Survival (drug effects)
• Humans
• Lymphoma (drug therapy, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Triterpenes (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays