篩選抑制神經膠母細胞瘤之中草藥

Abstract

多型性神經膠母細胞瘤 (GBM) 是最常見且惡性的原生性腦瘤。造成膠質母細胞瘤的原因目前還不明瞭，而現行的治療方法為結合手術、放射線與化學治療，但由於它具有高度的浸潤能力，以及對於放射線與化學治療的抵抗能力，造成疾病難以治癒並容易產生復發的狀況，這些可能是由多型性神經膠母細胞瘤的癌幹細胞引起的，故針對癌幹細胞為標靶可能是多型性膠母細胞瘤合適的治療方法。中草藥這個傳統的治療方法已在中國流傳千年之久，現今它不僅治療疾病，亦成為前景看好之生物技術產品。為了研究中草藥萃取物是否可以當作治療多型性神經膠母細胞瘤的潛力藥物，我們建立膠質母細胞瘤衍生之球細胞篩選平台，以此篩選四百種中草藥萃取物中可以有效抑制膠質母細胞瘤的細胞株的生長或存活之中草藥。目前已篩選出三種具潛力的藥物，可以有效抑制膠質母細胞瘤生長，但對於非轉型的正常細胞毒性較低。另外這些萃取物也會影響細胞移動的能力，並調控細胞ERK與AKT的訊息傳導、細胞週期與自噬作用等。另外，這些萃取物會更進一步抑制癌幹細胞的標記的表現。綜上所述，我們建立了一個多型性神經膠母細胞瘤的中草藥萃取物篩選平台，並篩選出三個有效抑制多型性神經膠母細胞瘤之萃取物，期望未來可發展為具潛力之候選藥物。Glioblastoma (glioblastoma multiforme, GBM) is the most common and aggressive malignant primary brain tumor in adults. It is notorious for its genetic, cellular and phenotypic heterogeneity, which makes the disease difficult to target. The existence of glioblastoma stem cells (GSC or glioblastoma-initiating cells) may account for the invasiveness and drug resistance of GBM and become a suitable target for developing new treatment for this malignant disease. Chinese herbal medicine is a traditional therapy and has been used widely in Chinese for few thousand years. Nowadays, it is not only important in disease treatment, but also becomes a promising biotech product remained to be revealed by evidence-based analysis. To investigate whether herbal extracts may serve as a new drug for the treatment of glioblastoma, especially targeting GSCs, we have set up a drug screening platform using human glioblastoma cell lines-derived tumorsphere cells to screen 400 herbal extracts. Three herbal extracts have been identified, which effectively inhibited the growth of GSCs but with low or no toxicity to non-transforming cells. In addition, these extracts also inhibited the spheroid formation and cell migration ability of GSCs. The expression levels of stem cell markers such as CD133 and Sox2 were also reduced by the treatments of these extracts. The signaling pathways affected by these extracts include Akt, ERK, cell cycle regulation and apoptosis. In conclusion, we have identified three effective Chinese herbal extracts which target GSCs effectively, and could be further developed as potential therapeutics of glioblastoma.