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    • GW 610 Many studies have demonstrated that

    2018-11-08

    Many studies have demonstrated that GSCs isolated from glioblastomas display a capacity for multiple-lineage differentiation (Hemmati et al., 2003; Matsuda et al., 2012; Singh et al., 2003, 2004; Sunayama et al., 2010b). When differentiated, these GW 610 usually lose the capacity for long-term cellular repopulation and fail to propagate tumors, suggesting that inducing differentiation in GSCs may be a practical strategy for eliminating the GSC population (Frank et al., 2010). In addition, the possibility that the differentiation of GSCs within a malignancy can lead to tumor degeneration and increased susceptibility to conventional cytotoxic therapies has been widely recognized (Frank et al., 2010). Thus, it is very important to elucidate the mechanisms underlying the control of stem cells and cancer stem cell differentiation. In this respect, several strategies have been reported to promote the differentiation of GSCs (Ikushima et al., 2009; Lee et al., 2008; Matsuda et al., 2012; Penuelas et al., 2009; Piccirillo et al., 2006; Sato et al., 2012; Sunayama et al., 2011). All these reports demonstrate that the promotion of GSC differentiation can markedly reduce their tumorigenicity and thereby control the GSC population per se, underscoring the idea that differentiation therapy is a promising approach to target GSCs. Resveratrol is a phytochemical found in many natural foods such as red wine, grapes, and peanuts (Baur and Sinclair, 2006). The antitumor effect of resveratrol has been demonstrated in many cancers, and it has been shown to regulate multiple stages of tumorigenesis, including the prevention of tumor initiation (Athar et al., 2007; Bishayee, 2009). While it is also well recognized that cancer stem cells play a key role in tumor initiation (Reya et al., 2001), the effects of resveratrol on cancer stem cells remain poorly understood. Nanog is considered a master transcriptional factor of embryonic stem cells (ESCs). Nanog expression is modulated at the transcriptional level, positively regulated by LIF-STAT3 and bone morphogenetic protein-Brachyury pathways, and negatively regulated by transcription factor 3 and p53 (Lin et al., 2005; Pan and Thomson, 2007). Recent evidence has suggested a shared characteristic between ESCs, cancer cells, and cancer stem cells (Boyer et al., 2005). Nanog may play important functions in the development and progression of malignant tumors; however, this has not been fully understood.
    Materials and methods
    Results
    Discussion The hypothesis that tumor cells with characteristics of stem cells are responsible for tumor initiation, recurrence, and therapeutic resistance is redirecting efforts against cancer (Dick, 2008; Zhou et al., 2009). To date, several molecular pathways for effective therapeutic targets against GSCs have been identified (Ikushima et al., 2009; Lee et al., 2008; Matsuda et al., 2012; Penuelas et al., 2009; Piccirillo et al., 2006; Sato et al., 2012; Wurdak et al., 2010; Zheng et al., 2010), but these agents are not applicable in a clinical setting. Importantly, resveratrol has received increasing attention for its potential therapeutic use, and several clinical trials are currently underway (NCT00256334, NCT00433576, and NCT00578396). However, in the cancer stem cell field, the molecular mechanisms and effects of resveratrol have been poorly understood to date. In this study, we have shown that resveratrol may be effective in controlling GSCs. In the present study, we found that resveratrol not only inhibits the self-renewal capacity of GSCs (reduced sphere formation and stem cell marker expression) and tumorigenicity but also promotes differentiation (increased differentiation marker expression). Recently, resveratrol was shown to induce apoptosis and suppress the growth of breast cancer stem-like cells in vivo (Pandey et al., 2011). In gliomas, resveratrol induced apoptosis and enhanced radiosensitivity of CD133-positive glioblastoma cells (Yang et al., 2012). However, these studies focused on the control of proliferation and enhancement of the sensitivity of cancer stem cells to radio- and chemotherapy; whether and how resveratrol regulated cancer stem cell characteristics were not addressed. Here, we demonstrated that the potential of resveratrol to differentiate GSCs into non-tumorigenic cells and the resveratrol-induced differentiation of these cells are important factors in inhibiting the tumor-initiating capacity of cancer stem cells.