Butein suppresses breast cancer growth by reducing a production of intracellular reactive oxygen species

Background: Butein has various functions in human diseases including cancer. While anti-cancer effects of butein have been revealed, it is urgent to understand a unique role of butein against cancer. In this study, we demonstrate that butein inhibition of reactive oxygen species (ROS) production results in suppression of breast cancer growth. Methods: Different breast cancer cell lines were treated with butein and then subjected to cell viability and apoptosis assays. Butein-sensitive or -resistant breast cancer cells were injected into mammary fat pads of immunocompromised mice and then butein was injected. Breast cancer cells were categorized on the basis of butein sensitivity. Results: Butein reduced viabilities of different breast cancer cells, while not affecting those of HER2-positive (HER2(+)) HCC-1419, SKBR-3 and HCC-2218 breast cancer cells. Butein reduction of ROS levels was correlated with apoptotic cell death. Furthermore, butein reduction of ROS level led to inhibitions of AKT phosphorylation. N-acetyl-L-cysteine (NAC), a free radical scavenger, also reduced ROS production and AKT phosphorylation, resulting in apoptotic cell death. In contrast, inhibitory effects of both butein and NAC on ROS production and AKT phosphorylation were not detected in butein-resistant HER2(+) HCC-1419, SKBR-3 and HCC-2218 cells. In the in vivo tumor growth assays, butein inhibited tumor growth of butein-sensitive HER2(+) BT-474 cells, while not affecting that of butein-resistant HER2(+) HCC-1419 cells. Moreover, butein inhibition of ROS production and AKT phosphorylation was confirmed by in vivo tumor growth assays. Conclusions: Our study first reveals that butein causes breast cancer cell death by the reduction of ROS production. Therefore, our finding provides better knowledge for butein effect on breast cancer and also suggests its treatment option.