Low-dose spiruchostatin-B, a potent histone deacetylase inhibitor enhances radiation-induced apoptosis in human lymphoma U937 cells via modulation of redox signaling.
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 [Formula: see text]). 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.
a Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama , Japan ;
Mati Ur
MU
Rehman
a Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama , Japan ;
Paras
P
Jawaid
a Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama , Japan ;
Qing Li
QL
Zhao
a Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama , Japan ;
Peng
P
Li
b Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University , Aoba-ku, Sendai , Japan ;
Koichi
K
Narita
b Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University , Aoba-ku, Sendai , Japan ;
Tadashi
T
Katoh
c Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama , Japan.
Tadamichi
T
Shimizu
a Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama , Japan ;
Takashi
T
Kondo
D017209:Apoptosis; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000378:metabolism*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D020298:U937 Cells
D047630:Depsipeptides; D017382:Reactive Oxygen Species; C529984:spiruchostatin B
Apoptosis; HDAC inhibitor; Spiruchoustatin B; radiation; reactive oxygen species (ROS)