Skyrin (SKR) is a plant bisanthraquinone secondary metabolite from the Hypericum genus with potential use in anticancer
therapy. However, its effect and mechanism of action are still unknown. The negative effect of SKR on HCT 116 and HT-29
cancer cell lines in hypoxic and normoxic conditions was observed. HCT 116 cells were more responsive to SKR treatment as demonstrated by decreased metabolic activity, cellularity and accumulation of cells in the G1 phase. Moreover, an increasing number of apoptotic cells was observed
after treatment with SKR. Based on the LC-MS comparative proteomic data from
hypoxia and normoxia (data are available via ProteomeXchange with the identifier PXD019995), SKR significantly upregulated
Death receptor 5 (DR5), which was confirmed by real-time qualitative PCR (RT-qPCR). Furthermore, multiple changes in the
Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL)-activated cascade were observed. Moreover, the reversion of TRAIL resistance was observed in HCT 116, HT-29 and SW620 cell lines, even in
hypoxia, which was linked to the upregulation of DR5. In conclusion, our results propose the use of SKR as a prospective anticancer
drug, particularly as an adjuvant to TRAIL-targeting treatment to reverse TRAIL resistance in
hypoxia.