Low-dose spiruchostatin-B, a potent histone deacetylase inhibitor enhances radiation-induced apoptosis in human lymphoma U937 cells via modulation of redox signaling

Abstract

Spiruchostatin B (SP-B), is a potent histone deacetylase (HDAC) inhibitor, in addition to HDAC inhibition, the pharmacological effects of SP-B are also attributed to its ability to produce intracellular reactive oxygen species (ROS), particularly H₂O₂. In this study, we investigated the effects of low dose (non-toxic) SP-B on radiation-induced apoptosis in human lymphoma U937 cells in vitro. The treatment of cells with low-dose SP-B induced the acetylation of histones, however, does not induce apoptosis. Whereas, the combined treatment with SP-B and radiation significantly enhanced the radiation-induced apoptosis, suggesting the potential role of this combined treatment for future radiation therapy. Interestingly, the enhancement of apoptosis was accompanied by significant increased in the ROS generation. Pre-treatment with an antioxidant, N-acetyl-l-cysteine (NAC) significantly inhibited the enhancement of apoptosis induced by combined treatment, indicating that ROS play an essential role. It was also found that SP-B combined with radiation caused the activation of death receptor and intrinsic apoptotic pathways, via modulation of ROS-mediated signaling. Moreover, SP-B also significantly enhanced the radiation-induced apoptosis in other lymphoma cell lines such as Molt-4 and HL-60. Taken together, our findings suggest that the low-dose SP-B enhances radiation-induced apoptosis via modulation of redox signaling because of its ability to serve as an intracellular ROS generating agent, mainly (H₂O₂ or ). This study provides further insights into the mechanism of action of SP-B with radiation and demonstrates that SP-B can be used as a future novel sensitizer for radiation therapy.

Keywords:

• Apoptosis
• HDAC inhibitor
• radiation
• reactive oxygen species (ROS)
• Spiruchoustatin B

Acknowledgements

This study was partially supported by Grant-in-Aid for Scientific Research (B) (15H04904), Japan Society for the Promotion of Science.

Declaration of interest

The authors declare that there are no conflicts of interest. The authors alone are responsible for the content and writing of the paper.