Abstract
High-risk neuroblastoma (NB) is lethal childhood cancer. Published data including ours have reported the anti-proliferative effect of Xanthohumol (XN), a prenylated chalcone, in various cancer types suggesting that XN could be a useful small molecule compound against cancer. The TNF-Related Apoptosis-Inducing Ligand (TRAIL) is an endogenous ligand that is expressed in various immune cells. TRAIL mediates apoptosis through binding of transmembrane receptors, death receptor 4 (DR4) and/or death receptor 5 (DR5). Cancer cells are frequently resistant to TRAIL-mediated apoptosis, and the cause of this may be decreased expression of death receptors. This study aimed to identify combination therapies that exploit XN for NB. First, the effect of XN on cellular proliferation in human NB cell lines NGP, SH-SY-5Y, and SK-N-AS were determined via MTT assay, colony forming assay, and real-time live cell imaging confluency. XN treatment causes a statistically significant decrease in the viability of NB cells with IC50 values of approximately 12 μM for all three cell lines. Inhibition of cell proliferation via apoptosis was evidenced by an increase in pro-apoptotic markers (cleaved PARP, cleaved caspase-3/-7, and Bax) and a decrease in an anti-apoptotic marker, Bcl-2. Importantly, XN treatment inhibited PI3K/Akt pathway and associated with increased expression of DR5 by both mRNA and protein levels. Furthermore, a statistically significant synergistic reduction was observed following combination treatment (50%) compared to either TRAIL (5%) or XN (15%) alone in SK-N-AS cells. Therefore, this study shows XN treatment reduces NB cell growth via apoptosis in a dose-dependent manner, and enhanced growth reduction was observed in combination with TRAIL. This is the first study to demonstrate that XN alters the expression of DR5 as well as the synergistic effect of XN on TRAIL in NB and provides a strong rationale for further preclinical analysis.
Highlights
Neuroblastoma (NB) is a devastating cancer of the sympathetic nervous system that predominantly strikes children [1, 2]
Another agent of interest is the TNF-related apoptosis-inducing ligand (TRAIL) cytokine which is expressed in various immune cells including CD4+ T cells, NK cells, macrophages, and dendritic cells and binds to death receptor 5 (DR5) to induce apoptosis [24]
In SK-N-AS and NGP cell lines, there was a significant reduction in colony formation with increasing concentrations of XN, beginning at concentrations greater than 10 μM which is depicted as a bar graph (Fig 2C)
Summary
Neuroblastoma (NB) is a devastating cancer of the sympathetic nervous system that predominantly strikes children [1, 2]. We reported that there was a delay in tumor progression in cholangiocarcinoma xenograft after XN treatment [13] Another agent of interest is the TNF-related apoptosis-inducing ligand (TRAIL) cytokine which is expressed in various immune cells including CD4+ T cells, NK cells, macrophages, and dendritic cells and binds to death receptor 5 (DR5) to induce apoptosis [24]. It was suggested that the activation of AKT may contribute to the development of TRAIL resistance in prostate cancer cells [32, 33]. Both XN and TRAIL have therapeutic potential, and this study looks at the effect of these compounds in NB cell lines
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