Identification of plant extracts sensitizing breast cancer cells to TRAIL

Triple-negative breast cancer (TNBC) is an aggressive heterogeneous cancer subgroup with a higher rate of distant recurrence and a poorer prognosis compared to other subgroups. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive molecule that induces cell death in various tumor cells without causing cytotoxicity to normal cells; however, primary or acquired resistance to TRAIL often limits its efficacy in cancer patients. To develop combination therapies to improve TRAIL efficacy and/or to overcome the resistant mechanism, we screened 138 medicinal plant extracts against TRAIL-sensitive and -insensitive TNBC cell lines, MDA-MB-231 and MDA-MB-468. Among them, 5 plant extracts, Uvaria dac, Artemisia vulgaris, Cortia depressa, Dichasia bengalensis and Cinnamomum obtusifolium did not cause apparent cytotoxicity (<20%) as a single regimen, but showed significant synergistic effects in combination with TRAIL against both cell lines. Moreover, Uvaria dac, Artemisia vulgaris and Cinnamomum obtusifolium were found to suppress the phosphorylation of p65 that is involved in TRAIL-resistant mechanisms. These observations suggest that the identified plant extracts in combination with TRAIL could lead to potential therapeutic benefits for cancer patients in the clinical setting.