Abstract
Most tumors maintain elevated levels of polyamines to support their growth and survival. This study explores the anti-tumor effect of polyamine starvation via both inhibiting polyamine biosynthesis and blocking the upregulated import of polyamines into the tumor. We demonstrate that polyamine blockade therapy (PBT) co-treatment with both DFMO and a novel polyamine transport inhibitor, Trimer PTI, significantly inhibits tumor growth more than treatment with DFMO or the Trimer PTI alone. The anti-tumor effect of PBT was lost in mice where CD4+ and CD8+ T cells were antibody depleted, implying that PBT stimulates an anti-tumor immune effect that is T-cell dependent. The PBT anti-tumor effect was accompanied by an increase in granzyme B+, IFN-γ+ CD8+ T-cells and a decrease in immunosuppressive tumor infiltrating cells including Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs), CD4+CD25+ Tregs, and CD206+F4/80+ M2 macrophages. Stimulation with tumor-specific peptides elicited elevated antigen-specific IFN-γ secretion in splenocytes from PBT-treated mice, indicating that PBT treatment stimulates the activation of T-cells in a tumor-specific manner. These data show that combined treatment with both DFMO and the Trimer PTI not only deprives polyamine-addicted tumor cells of polyamines, but also relieves polyamine-mediated immunosuppression in the tumor microenvironment, thus allowing the activation of tumoricidal T-cells.
Highlights
Cancer cells develop many diverse and complex mechanisms to evade the effects of chemotherapeutics, drugs that target a specific signaling pathway [1]
There was a significant inhibitory effect on tumor growth in mice treated with both DFMO and the Trimer polyamine transport inhibitor (PTI) with a 4-fold reduction in final tumor weight compared to vehicle treated mice
Treatment with DFMO alone reduced the levels of putrescine compared to vehicle-treated mice, whereas treatment with Trimer PTI alone had no discernible effect on polyamine levels (Figure 2D)
Summary
Cancer cells develop many diverse and complex mechanisms to evade the effects of chemotherapeutics, drugs that target a specific signaling pathway [1]. This chemoresistance remains a significant obstacle to successful cancer therapy. Intracellular polyamine levels are maintained via tightly-regulated biosynthetic, catabolic, and uptake and export pathways [13]. Oncogenes such as MYC and RAS both upregulate polyamine biosynthesis [17,18,19] and increase cellular uptake of polyamines by inducing the polyamine transport system (PTS) [20, 21]. In order to meet their huge metabolic needs, most tumors have a greatly increased need for polyamines compared to normal cells and, polyamines are potent modifiers of tumor development [22]
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