Andrographolide elevates tumor necrosis factor-related apoptosis-inducing ligand lethality through reactive oxygen species accumulation and gasdermin E cleavage in breast cancer cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is selectively lethal to cancer cells and harmless to normal cells, making it a potential agent for cancer therapy. However, some breast cancer cells are resistant to TRAIL. This study revealed that andrographolide (Andro), an extract from Andrographis paniculate , a natural compound, sensitized breast cancer cells to TRAIL-induced tumor suppression; it identified apoptosis-associated protein regulation, reactive oxygen species accumulation, mitochondria membrane potential disruption, caspase cascade activation, and gasdermin-E cleavage to be involved in the tumor lethality mediated by Andro combined with TRAIL treatment. The flow cytometry results showed the combination of Andro and TRAIL repressed breast cancer cells by cell death induction, and the assessment of combined index indicated that the combined treatment with Andro and TRAIL repressed breast cancer cells synergistically. Blotting results displayed Andro and TRAIL combination elevated TRAIL-associated receptors, death receptors 4 and 5, at protein levels. These results provided critical insight into breast cancer patients’ therapy and exploration direction for TRAIL clinical application.