title: 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.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, 29425, South Carolina; Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, 29425, South Carolina; Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, 29425, South Carolina.
authors.forename: Faisal F Y
authors.initials: FF
authors.lastname: Radwan
authors.forename: Azim
authors.initials: A
authors.lastname: Hossain
authors.forename: Jason M
authors.initials: JM
authors.lastname: God
authors.forename: Nathan
authors.initials: N
authors.lastname: Leaphart
authors.forename: Michelle
authors.initials: M
authors.lastname: Elvington
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Azizul
authors.initials: A
authors.lastname: Haque
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014315:Triterpenes; C556862:ganoderic acid
keywords: APOPTOSIS; CASPASES; HLA CLASS II PROTEINS; LYMPHOMA; MITOCHONDRIA; MYELOID-DERIVED SUPPRESSOR CELLS; STAT3; T CELLS; TRITERPENOID