title: 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 investigatedin vitrousing recombinant TRAIL andin vivousing 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 apoptosisin 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.
authors.affiliation: Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Alaa
authors.initials: A
authors.lastname: Refaat
authors.forename: Sherif
authors.initials: S
authors.lastname: Abdelhamed
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hiroki
authors.initials: H
authors.lastname: Inoue
authors.forename: Satoru
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
keywords: TNF-related apoptosis-inducing ligand; apoptosis; berberine; breast cancer; coptisine