Demethoxycurcumin was superior to temozolomide in the inhibition of the growth of glioblastoma stem cells in vivo
Demethoxycurcumin was superior to temozolomide in the inhibition of the growth of glioblastoma stem cells in vivo
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DOI：
10.1007/s13277-016-5399-x
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发表时间：
2016-12-01
期刊：
影响因子：
--
通讯作者：
Shi, Lei
中科院分区：
文献类型：
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作者：
Leng, Liang;Zhong, Xiaojun;Shi, Lei
替莫唑胺(TMZ)被广泛用于治疗多形性胶质母细胞瘤(GBM)，因为它能有效地抑制GBM的生长几个月，但这种癌症仍然是无法治愈的。胶质瘤干细胞(GSCs)的存在被认为是治疗后GBM持续复发的原因，但GSCs对TMZ不敏感。我们最近的研究表明，姜黄素的一种成分去甲氧基姜黄素(DMC)在体外抑制GSCs增殖和诱导GSCs凋亡的能力优于TMZ。此外，TMZ+DMC联合治疗可诱导更明显的抗GSC作用。然而，在本研究中，TMZ+DMC在体内没有发现明显的协同抗GSC作用，而DMC在体内对GSC的生长抑制作用仍然优于TMZ。此外，增殖细胞核抗原的免疫组织化学显示，这种抑制作用主要与抑制细胞增殖有关，而与细胞凋亡无关。然而，根据末端脱氧核苷酸转移酶dUTP缺口末端标记(TUNEL)分析，高浓度的DMC(50 mg/kg)单独或与TMZ联用也可诱导约10%的细胞发生凋亡。最后，对其潜在机制的研究表明，Janus激酶(JAK)/信号转导和转录激活因子(STAT)3信号通路在抗GSC效应中起着重要作用。当应用JAK抑制剂AG490时，DMC的抗GSC作用增强。综上所述，本研究表明DMC在体内抗GSC作用优于TMZ，其抗GSC作用是通过抑制JAK/STAT3通路的激活而实现的，而DMC与TMZ之间没有协同作用。
Temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM) as it can effectively inhibit the growth of GBM for some months; however, this cancer type is still incurable. The existence of glioma stem cells (GSCs) is thought to be responsible for the invariable recurrence of GBM after treatment, but GSCs are insensitive toTMZ. Our recent research showed that demethoxycurcumin (DMC), a component of curcumin, was superior to TMZ in its ability to inhibit proliferation and induce apoptosis of GSCs in vitro. In addition, the combined treatment of TMZ + DMC induced more obvious anti-GSC effects. However, in this study, no obvious synergistic anti-GSC effects of TMZ + DMC were found in vivo, while DMC was still superior to TMZ with respect to growth inhibition of GSCs in vivo. Furthermore, immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed that such inhibitory effects were mainly related to the inhibition of cell proliferation rather than to apoptosis. However, a high concentration of DMC (50 mg/kg) alone or combined with TMZ could also induce approximately 10 % of the cells to undergo apoptosis according to a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Finally, an investigation of the underlying mechanism revealed that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) 3 signaling pathway played an important role in the anti-GSC effects. When the JAK inhibitor AG490 was applied, the anti-GSC effects of DMC were enhanced. Taken together, the present work reveals that DMC is superior to TMZ with respect to its anti-GSC effects in vivo, which are mediated through the inhibition of the activation of the JAK/STAT3 pathway; however, DMC demonstrated no synergistic effects with TMZ.