Yang Liuqi, Guo Huijie, Dong Lihua, Wang Li, Liu Chunlan, Wang Xiujie
Laboratory of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Oncol Rep. 2014 Sep;32(3):1303-11. doi: 10.3892/or.2014.3293. Epub 2014 Jun 26.
Glioma stem cells (GSCs) are believed to contribute to glioblastoma multiforme (GBM) propagation and treatment resistance. Tanshinone IIA possesses anticancer and anti-inflammatory activities. This study aimed to determine the inhibitory effect of tanshinone IIA on human GSCs in vitro and in vivo and to explore the underlying mechanisms. In the present study, human GBM neurospheres (GBMS) were isolated from adherent GBM cells in serum-free medium, and the cells from the GBMS displayed characteristics of GSCs. Results from the MTT, neurosphere formation and in vivo inhibition assays revealed that tanshinone IIA had a significant inhibitory effect on human GSCs in vitro and in vivo. Furthermore, tanshinone IIA increased the expression of differentiation and neural lineage markers including GFAP and β-tubulin, decreased expression of GSC markers including CD133 and nestin, and induced GSC apoptosis in vitro and in vivo in a dose‑dependent manner. Inflammatory cytokines and signaling pathways are believed to play key roles in maintaining the stem-like properties in human glioma cells. In the present study, inflammatory cytokine interleukin 6 (IL6) and its downstream activated signal transducer and activator of transcription 3 [phospho-STAT3(tyrosine705) and phospho-STAT3(serine727)] were downregulated after tanshinone IIA treatment in vitro and in vivo. This result indicated that disturbance of the IL6/STAT3 signaling axis by tanshinone IIA is closely related to the growth inhibition of GSCs. Taken together, our results indicate that tanshinone IIA has the potential to target and kill GSCs through suppression of proliferation, attenuation of stemness and induction of apoptosis. Its mechanism of activity may be associated with attenuation of the IL6/STAT3 signaling pathway.
胶质瘤干细胞（GSCs）被认为与多形性胶质母细胞瘤（GBM）的增殖和治疗抗性有关。丹参酮IIA具有抗癌和抗炎活性。本研究旨在确定丹参酮IIA在体外和体内对人GSCs的抑制作用，并探索其潜在机制。在本研究中，在无血清培养基中从贴壁的GBM细胞中分离出人GBM神经球（GBMS），并且来自GBMS的细胞表现出GSCs的特征。MTT、神经球形成和体内抑制试验的结果表明，丹参酮IIA在体外和体内对人GSCs具有显著的抑制作用。此外，丹参酮IIA增加了包括GFAP和β-微管蛋白在内的分化和神经谱系标志物的表达，降低了包括CD133和巢蛋白在内的GSC标志物的表达，并在体外和体内以剂量依赖性方式诱导GSC凋亡。炎症细胞因子和信号通路被认为在维持人胶质瘤细胞的干细胞样特性中起关键作用。在本研究中，炎症细胞因子白细胞介素6（IL6）及其下游活化的信号转导和转录激活因子3[磷酸化STAT3（酪氨酸705）和磷酸化STAT3（丝氨酸727）]在体外和体内经丹参酮IIA处理后下调。该结果表明，丹参酮IIA对IL6/STAT3信号轴的干扰与GSCs的生长抑制密切相关。综上所述，我们的结果表明，丹参酮IIA具有通过抑制增殖、减弱干性和诱导凋亡来靶向和杀死GSCs的潜力。其活性机制可能与IL6/STAT3信号通路的减弱有关。
