title: Novel N-amidinopiperidine-based proteasome inhibitor preserves dendritic cell functionality and rescues their Th1-polarizing capacity in Ramos-conditioned tumor environment.
abstract: The tumor microenvironment represents a burden that hampers the proper activation of immune cells, including the dendritic cells (DCs). It is, therefore, desired that the important characteristics of a given anticancer drug candidate be seen as consisting not solely of its antitumor properties, but that it also lacks potential side effects that could additionally constrain the development and function of immune cells associated with tumor immunity. We have previously identified compounds with a N-amidinopiperidine scaffold that selectively induce apoptosis in Burkitt's lymphoma cells through proteasome inhibition. Here, we demonstrate that SPI-15 affected neither the viability of DCs nor their differentiation. In addition, the compound had no significant effect on their cytokine secretion or allostimulatory capacity. Moreover, DC functionality in the context of tumor microenvironment was also unaffected, as demonstrated by experiments performed on DCs differentiated in Ramos-conditioned media in the presence or absence of SPI-15. The cytokine profile and functional assays revealed that SPI-15 rescues DC differentiation from the immunosuppressive environment produced by Ramos cells; this was seen by their reacquired ability to induce IFN-γ-secretion from naïve CD4(+)CD45RA(+) T cells and the consequently induced Th1-effector differentiation. Herein, we present novel characteristics of an N-amidinopiperidine-based protease inhibitor whose anticancer properties are not associated with the immunosuppression of DCs. We propose future studies toward the design of structurally similar compounds with the aim of developing potent anticancer drugs with minimal negative effects on crucial factors involved in tumor immunity.
authors.affiliation: Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, 1000, Ljubljana, Slovenia, svajgerurban@yahoo.com.
authors.forename: Urban
authors.initials: U
authors.lastname: Švajger
authors.forename: Martina
authors.initials: M
authors.lastname: Gobec
authors.forename: Aleš
authors.initials: A
authors.lastname: Obreza
authors.forename: Irena
authors.initials: I
authors.lastname: Mlinarič-Raščan
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D018417:Th1 Cells / Q000276:immunology*; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000578:Amidines; D000970:Antineoplastic Agents; D016207:Cytokines; D010880:Piperidines; D061988:Proteasome Inhibitors; C000596025:SPI-15 compound; C032727:piperidine; D046988:Proteasome Endopeptidase Complex