Berberine enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast cancer

Abstract

Berberine (BBR) has been used for the treatment of bacterial and fungal infections and also for cancer‑associated symptoms such as diarrhea. Furthermore, it has been reported that BBR may have direct antitumor effects. Although evidence supports the theory that tumor necrosis factor (TNF)‑related apoptosis‑inducing ligand (TRAIL) is a promising candidate for treating cancer, its usage may be limited due to the resistance to the TRAIL‑induced apoptosis of cancer cells. In the present study, the effect of BBR on TRAIL‑induced antitumor effects was investigated in vitro using recombinant TRAIL and in vivo using a 4T1 murine breast cancer model in combination with anti‑DR5 (death‑inducing TRAIL receptor) monoclonal antibody therapy. BBR sensitized human breast cancer cell lines to TRAIL‑mediated apoptosis in vitro. The combination of BBR and recombinant TRAIL significantly activated caspase‑3 and PARP cleavage in TRAIL‑resistant MDA‑MB‑468 cells. Furthermore, BBR in combination with TRAIL more effectively induced apoptosis compared with coptisine (COP), which is structurally related to BBR. In a murine 4T1 breast cancer model, BBR treatment enhanced the efficacy of anti‑DR5 antibody therapy against primary tumor growth and lung metastasis. Thus, BBR may become a new adjuvant for overcoming the resistance of cancer cells to TRAIL/DR5‑mediated therapy.