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Aim and objective: Although the clinical significance of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been elucidated, primary or acquired resistance to TRAIL limits its efficacy in cancer patients. This study aimed to investigate bufadienolides as promising candidates to combine with TRAIL and to determine the pathway involved in overcoming TRAIL resistance in breast cancer cells. Methods: The effects of bufadienolides, cinobufagin and cinobufotalin, in combination with TRAIL were examined in TRAIL-sensitive and TRAIL-resistant breast cancer, MDA-MB-231 and MDA-MB-468 cells, respectively. Cell viability was determined using count and viability assays. Apoptotic cell death was detected by annexin-V/7-AAD staining. Silencing of MCL-1 expression was established using MCL-1 siRNA and protein expression was assessed by Western blot analysis. STAT3 localization was determined using immunofluorescence staining. Results: The combination of bufadienolides with TRAIL significantly reduced cell viability in both TRAIL-sensitive and TRAIL-resistant breast cancer cells in vitro. Bufadienolides overcame TRAIL resistance by downregulating MCL- 1, an anti-apoptotic protein, through the JAK-STAT pathway. The combination of TRAIL with knock down of MCL-1 or JAK-STAT inhibitor, JSI-124, could synergistically induce apoptosis similar to bufadienolides. Conclusion: Bufadienolides enhance TRAIL-induced apoptosis in breast cancer cells through Mcl-1 downregulation via JAK-STAT pathway. Targeting MCL-1 or JAK2 could be one of the strategies to overcome breast cancer cell resistance to TRAIL. Bufadienolides, through JAK2/STAT3/MCL-1 inhibition, could be considered as promising cancer therapy agents in combination with TRAIL.

Bufadienolides Overcome TRAIL Resistance in Breast Cancer Cells via JAK-STAT Pathway