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    • wst-1 assay The animal model described here is also expected

    2019-04-22

    The animal model described here is also expected to lead us to design mechanism-based therapeutic interventions for bone metastases of NB. In this context, it is notable that the selective COX-2 inhibitor NS-398, which is known to selectively inhibit COX-2 without affecting COX-1 activity [30], inhibited bone metastases of SK-N-AS cells. Consistent with the results described here, we reported that NS-398 significantly reduced osteolytic bone metastases of MDA-MB-231 human breast cancer wst-1 assay [12]. Moreover, Sabino et al. [31] described that NS-398 not only decreased 2472 sarcoma colonization in bone and bone destruction but also bone pain associated with tumor growth, suggesting an additional potential beneficial effect of COX-2 inhibitors for NB treatment. Bone pain is one of the most common and devastating complications in bone metastases in children with NB [32]. Another notable finding in our study is that NS-398 inhibited not only bone metastases but also adrenal metastases. Adrenal gland is a preferential site for NB to initiate and expand, which leads to death [1,2]. Thus, selective COX-2 inhibitors may have beneficial effects on not only quality of life but survival in infants with NB. Clinical studies also reported that the selective COX-2 inhibitor celecoxib prevented the occurrence of colorectal adenomas [33] and showed some therapeutic effects in patients with breast [34], head and neck [35], cervical [36], non-small cell lung [37], colorectal [38] and ovarian cancer [39]. Of note, a recent clinical study described that oral celecoxib prevented the progression of neuroblastoma [40]. Further experimental and clinical studies are needed to verify the beneficial effects of selective COX-2 inhibitors for the treatment of infants with NB. The NB model described here would provide with a suitable preclinical model to conduct these studies. Since the selective COX-2 inhibitor NS-398 did not inhibit the proliferation of SK-N-AS cells in vivo and in vitro, we reasoned that the agent suppressed tumor-associated angiogenesis. Angiogenesis is essential for tumor cells to initiate, grow, survive, invade and spread [41]. VEGF, a specific mitogen for neovascularization, is a major factor in the promotion of tumor angiogenesis and growth of human cancers [42]. The importance of VEGF expression associated with angiogenesis in tumor behavior is also suggested in NB [43]. Several recent experimental studies have reported that COX-2 inhibitors inhibit tumor angiogenesis through down-regulation of VEGF expression, thereby suppressing tumor growth in breast [44], colorectal [45] and pancreatic cancer [46]. Furthermore, it has been shown that celecoxib combined with irinotecan inhibits the growth of neuroblastoma xenografts through induction of apoptosis and suppression of angiogenesis with decreased VEGF expression [47]. Consistent with these previous studies, we found that NS-398 decreased vascularization and VEGF-A expression in subcutaneous SK-N-AS tumors. COX-2/PGE2 is a well-known stimulator of angiogenesis [44–46]. Collectively, these results suggest that the inhibition by NS-398 of subcutaneous tumor growth and bone metastases of SK-N-AS NB is due to the suppression of VEGF and angiogenesis. Based on the pathophysiology bone metastasis [8,9], inhibition of osteoclastic bone resorption is a mechanism-based treatment for bone metastases regardless of cancer type. Bisphosphonates (BPs), which are potent and specific inhibitors of osteoclastic bone resorption, have been widely used for the treatment of bone metastases [48]. An experimental animal study reported that the BP ibandronate inhibited osteolytic bone lesions developed after intra-femoral injection of NB cells [49]. However, caution is required for the use of BPs for the treatment of bone metastases of NB children, since administration of BP may have adverse effects on skeletal growth in growing infants [50]. In this context, COX-2 inhibitors could be an alternative agent in the management of bone metastases in infants with NB with less adverse effects on skeletal growth.