Conventional
cytostatic cancer treatments rarely result in the complete eradication of
tumor cells. Therefore, new therapeutic strategies focus on antagonizing the immunosuppressive activity of established
tumors. In particular, recent studies of
antigen-loaded dendritic cells (DCs) eliciting a specific antitumor immune response has raised the hopes of achieving the complete elimination of
tumor tissue.
Genistein,
fingolimod and
betulin have already been described as active compounds in different types of
cancer. Herein, we applied an integrated screening approach to characterize both their
cytostatic and their immune-modulating properties side-by-side. As will be described in detail, our data confirmed that all three compounds exerted proapoptotic and antiproliferative activity in different
B16 melanoma cell lines to a given extent, as revealed by an MTT assay,
CFSE and
DAPI staining. However, while
genistein and
fingolimod also affected the survival of primary bone marrow (BM) derived DCs of C57BL/6 mice,
betulin exhibited a lower cytotoxicity for BMDCs in comparison to the
melanoma cells. Moreover, we could show for the first time, that only
betulin caused a simultaneous, highly specific immune-stimulating activity, as measured by the IL-12p70 release of
Toll-like receptor 4-stimulated BMDCs by ELISA, which was due to increased
IL-12p35 mRNA expression. Interestingly, the activation of DCs resulted in enhanced T lymphocyte stimulation, indicated by increased
IL-2 and IFN-γ production of cytotoxic T cells in spleen cell co-culture assays which led to a decreased viability of B16 cells in an
antigen specific model system. This may overcome the immunosuppressive environment of a
tumor and destroy
tumor cells more effectively in vivo if the immune response is specific targeted against the
tumor tissue by
antigen-loaded dendritic cells. In summary,
cytostatic agents, such as
betulin, that simultaneously exhibit immune stimulatory activity may serve as lead compounds and hold great promise as a novel approach for an integrated
cancer therapy.