title: Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling.
abstract: Bioactive phytochemicals from natural products, such as black raspberries (BRB; Rubus occidentalis), have direct anticancer properties on malignant cells in culture and in xenograft models. BRB components inhibit cancer progression in more complex rodent carcinogenesis models. Although mechanistic targets for BRB phytochemicals in cancer cells are beginning to emerge, the potential role in modulating host immune processes impacting cancer have not been systematically examined. We hypothesized that BRB contain compounds capable of eliciting potent immunomodulatory properties that impact cellular mediators relevant to chronic inflammation and tumor progression. We studied both an ethanol extract from black raspberries (BRB-E) containing a diverse mixture of phytochemicals and two abundant phytochemical metabolites of BRB produced upon ingestion (Cyanidin-3-Rutinoside, C3R; Quercitin-3-Rutinoside, Q3R). BRB-E inhibited proliferation, and viability of CD3/CD28 activated human CD4(+) and CD8(+) T lymphocytes. BRB-E also limited in vitro expansion of myeloid-derived suppressor cells (MDSC) and their suppressive capacity. Pre-treatment of immune cells with BRB-E attenuated IL-6-mediated phosphorylation of signal transducer and activator of transcription-3 (STAT3) and IL-2-induced STAT5 phosphorylation. In contrast, pre-treatment of immune cells with the C3R and Q3R metabolites inhibited MDSC expansion, IL-6-mediated STAT3 signaling, but not IL-2-induced STAT5 phosphorylation and were less potent inhibitors of T cell viability. Together these data indicate that BRB extracts and their physiologically relevant metabolites contain phytochemicals that affect immune processes relevant to carcinogenesis and immunotherapy. Furthermore, specific BRB components and their metabolites may be a source of lead compounds for drug development that exhibits targeted immunological outcomes or inhibition of specific STAT-regulated signaling pathways.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, 302B Comprehensive Cancer Center, 400 W. 12th Ave., Columbus, OH, 43210, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mace
authors.forename: Samantha A
authors.initials: SA
authors.lastname: King
authors.forename: Zeenath
authors.initials: Z
authors.lastname: Ameen
authors.forename: Omar
authors.initials: O
authors.lastname: Elnaggar
authors.forename: Gregory
authors.initials: G
authors.lastname: Young
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Riedl
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schwartz
authors.forename: Steven K
authors.initials: SK
authors.lastname: Clinton
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Knobloch
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Weghorst
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects; D005638:Fruit / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D065856:Rubus / Q000737:chemistry* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D007376:Interleukin-2; D010936:Plant Extracts; D050799:STAT5 Transcription Factor; D053612:Janus Kinases