摘要
胶质母细胞瘤(glioblastoma,GBM)占颅内肿瘤的12-15%。该肿瘤的治疗方法主要是包括外科手术,它呈弥漫性浸润的生长特性限制了外科手术的发挥而不能达到真正意义上的完全切除,因此,术后放疗和化疗等辅助治疗对提高患者生存期具有重要意义。虽然近些年GBM的常规疗法(主要是手术切除和化学药物治疗)得以明显改良,其预后依然严峻,患者的平均术后寿命(或初次诊断后寿命)常不超过1年。胶质母细胞瘤在肿瘤形成过程中受一些功能失活的抑癌基因和一些过度激活的原癌基因的影响,瘤细胞生理状态的细胞凋亡和细胞周期的既有平衡遭到破坏。因此,深入研究开发基于诱导肿瘤细胞凋亡治疗的新型抗肿瘤药物是非常必要的。研究表明,天然药材中提取的皂甙类化合物是极富希望的。
ArdipusillosideI[3-O-(α-L-rhamnopyranosyl-(1→2)- -D-glucopyranosyl-(1→3)- (β-D-glucopyranosyl-(1→2))- -L-arabinopyranosyl)-cyclamiretin A]是从朱砂根(Ardisia pusilla A.DC,紫金牛科)中提取出来的具有抗炎症潜能的自然三萜五环皂苷。既往研究表明,ArdipusillosideI能够抑制多种肿瘤细胞的生长并诱导瘤细胞凋亡,包括宫颈腺癌细胞(HeLa细胞),Lewis肺癌细胞和HepG2肝癌细胞,这表明该皂苷具有潜在的抗肿瘤特性;在Hela细胞中,细胞内游离钙的超载参与了它诱导肿瘤细胞凋亡的生化作用。
细胞凋亡,又称程序性细胞死亡,是一个高度保守,受机体严格控制的细胞自杀过程,是在许多不同的细胞内外生理事件调控下的清除衰老和突变细胞的正常生理功能。细胞凋亡存在两条途径,线粒体凋亡途径和死亡受体凋亡途径。线粒体途径的特点在于线粒体跨膜电位的去极化和细胞色素C的释放。死亡受体途径由Fas[肿瘤坏死因子(TNF)超家族的一种作用于细胞表面死亡受体的细胞因子]以及它的下游效应分子caspase-3的相继激活介导活化。Fas主要表达于肿瘤细胞表面作为受体介导细胞凋亡,其主要配体为FasL。Fas的细胞内结构域募集匹配分子如Fas相关死亡域(Fas-associatedDeath Domain,FADD)从而加快死亡诱导信号复合物(Death-inducingSignaling Complex,DISC)的形成。DISC形成后进一步募集Caspase-8前体并促进它们分子间的自发性裂解激活,从而活化的Caspase-8并激活下游的蛋白水解酶。在细胞凋亡过程中,各细胞器因为存在含天门冬氨酸的特殊位点而被众多活化的蛋白水解酶和核酸内(外)切酶靶向性水解,从而导致细胞发生凋亡特异性的生化和形态学改变。
在本研究中,我们观察了ArdipusillosideⅠ对胶质母细胞瘤细胞株U87MG细胞和原代培养的人源性胶质母细胞瘤细胞的诱导凋亡治疗作用,并探讨了其内在的效应机制。ArdipusillosideⅠ以时间和浓度依赖的方式显著抑制了瘤细胞的增殖活性,IC50大致相近,约4.05μM。ArdipusillosideⅠ治疗后的瘤细胞在显微镜下显示出明显的凋亡特征,包括染色质浓缩边集,细胞核分裂;这表明ArdipusillosideⅠ诱导了瘤细胞凋亡。ArdipusillosideⅠ治疗逐渐增加了两种胶质母细胞瘤细胞中处于亚G1细胞周期(凋亡期)的比例,并使瘤细胞周期阻滞于S期(DNA合成期)。此外,实验观察到ArdipusillosideⅠ增强了瘤细胞表面Fas受体及其配体FasL的表达,并激活Caspase-8和Caspase-3两大特异性蛋白水解酶。我们还注意到,随着FasL中和抗体的加入,Fas的激活被竞争性抑制之后,瘤细胞的凋亡率显著下降;而当我们用Caspase-8的特异性抑制剂z-IETD-fmk阻断了Caspase-8的激活之后,瘤细胞的凋亡几乎不受影响。这表明ArdipusillosideⅠ通过一种不依赖于Casepase-8的FasL/Fas信号介导的死亡受体途径诱导了瘤细胞的凋亡。上述结果表明,ArdipusillosideⅠ是一种能够诱导胶质母细胞瘤细胞凋亡的可靠的抗肿瘤药物。
我们的研究不仅证实了ArdipusillosideⅠ可以诱导U87MG细胞株和原代培养的胶质母细胞瘤株发生细胞凋亡的抗肿瘤作用,也明确了ArdipusillosideⅠ在治疗剂量窗内不会对非肿瘤性质的脑内大量存有的发挥支持细胞作用的胶质细胞SVGp12细胞株的生物活性和增殖构成危害我们用MTT法评估了ardipusillosideⅠ对人胶质母细胞瘤U87MG细胞、原代培养人源性胶质母细胞瘤和星形胶质SVGp12细胞的影响。统计结果表明ArdipusillosideⅠ以时间和浓度依赖的方式显著抑制了人胶质母细胞瘤U87MG细胞和原代培养人源性GBM细胞的增殖活性,与对照组相比,处理组瘤细胞OD值下降(P<0.05)。ArdipusillosideⅠ并不影响代表脑内主要的支持细胞的星形胶质SVGp12细胞的活力,与对照组相比,处理组神经胶质细胞OD值无明显改变(P>0.05)。这样,作为一种可望推向临床应用的化疗药物,ArdipusillosideⅠ的生物安全性得到了较大的保证。而我们所鉴定的ArdipusillosideⅠ通过一种不依赖于Casepase-8的FasL/Fas信号介导的死亡受体途径发挥抗肿瘤作用的分子机制又为我们开发针对相应效应分子的靶向性基因治疗药物提供了实验准备,从而更好地促进ArdipusillosideⅠ辅助药物的研发,完善该药物的临床应用方案。
Glioblastoma accounts for 12-15% of intracranial tumors. Effective treatmentis complicated by multiple factors, including the diffusely infiltrative nature ofthe disease, which limits complete surgical resection. Although conventionaltreatments have improved significantly, the prognosis for glioblastoma patients isgrim. Average life expectancy after initial diagnosis is usually no more than 1year. Glioblastoma carcinogenesis occurs following the functional inactivation ofseveral tumor suppressor genes with parallel activation of key oncogenes bymutations, which affect the apoptosis and cell cycle. Thus, intensive research hasbeen conducted to develop novel anticancer agents that induce cancer cellapoptosis. Saponins extracted from natural plants are among the most promising.
Ardipusilloside I [3-O-(α-L-rhamnopyranosyl-(1→2)- -D-glucopyranosyl-(1→3)-(β-D-glucopyranosyl-(1→2))- -L-arabinopyranosyl)-cyclamiretin A], anaturally occurring saponin with anti-inflammatory properties, is isolated fromArdisia pusilla A. DC, a member of the Myrsinaceae family. Primary studies in vivo and in vitro showed that ardipusilloside I inhibits the growth of, and inducesapoptosis in, human cervical adenocarcinoma cells (HeLa), Lewis pulmonarycarcinoma and hepatocarcinoma, demonstrating the potential anticancerproperties of this compound. The mechanisms by which these effects areachieved are not understood fully, although, in HeLa cells, they do involve anincrease of intracellular free calcium.
Apoptosis, or programmed cell death, is a highly conserved, tightly controlledcell suicide process that is regulated by many different intracellular andextracellular events to ablate neoplastic cells in normal physiological functions.Apoptosis is controlled by two potential pathways, the mitochondrial pathwayand the death receptor pathway. The mitochondrial pathway is characterized bythe loss of mitochondrial transmembrane potential and release of cytochrome c.The death receptor pathway is mediated by serial activation of Fas [a cell surfacedeath receptor of the tumor necrosis factor (TNF) family of cytokines] and theresultant effector caspase-3. Fas is a cell-surface receptor that mediates apoptoticcell death when triggered mainly by its lgand FasL. The intracellular domains ofFas recruit adapter molecules such as Fas-associated death domain (FADD), thusaccelerating the formation of a death-inducing signaling complex (DISC). DISCformation, in turn, recruits catalytically inactive procaspase-8 to allowintermolecular autocatalytic cleavage, thus releasing active caspase-8 to activatedownstream procaspases. During apoptosis process, cells are degraded by thecleavage of cellular substrates at specific sites containing aspartic acid and thenresult in the biochemical and morphological changes associated with apoptosisthrough the activation of proteases and endonucleases which catalyze key steps inthe death pathway.
Herein, we investigated its effect on glioblastoma cell line U87MG cells and primary cultured human glioblastoma cells, and examined the underlyingmechanism of action. Ardipusilloside I substantially decreased the number ofviable cells of both cell lines in a time- and concentration-dependent manner,with a similar IC_(50) of 4.05μM. Microscopy revealed apoptotic characteristics,including chromatin condensation and cell nucleus fragmentation, demonstratingthat ardipusilloside I induced apoptosis. Ardipusilloside I exposure also graduallyincreased the sub-G1 fraction (the apoptotic cell population) and an Sphase-arrest of both glioblastoma cells. Furthermore, ardipusilloside I increasedthe expression of Fas and its ligand (FasL), and enhanced the activation ofcaspase-8 and caspase-3. Additionally, we observed a significant decreasedapoptosis after the trigger effection of FasL was abolished by the neutralizationantibody anti-FasL antibody and an unchanged apoptosis level when theactivation of caspase-8 was interrupted by specific inhibitor z-lETD-fmk, whichsuggested that a casepase-8 independent FasL/Fas signaling mediated deathreceptor pathway is involved. These data suggested that ardipusilloside I could bedeveloped as a chemotherapeutic agent for the management of glioblatomas.
The current study not only confirms the induction of apoptosis byardipusilloside I in both glioblastoma U87MG cells and primary culturedglioblastoma cells, but also clearly demonstrates the minor effect ardipusilloside Iwith a concentration within the therapeutical dose-window has on the viability ofthe nonneoplastic astrocyte line SVGp12 which presented the supporting cellsthat are generously existed in brain parenchyma. The effect of ardipusilloside I onthe viability of U87MG cells, primary cultured glioblastoma cells and SVGp12astrocytes was assessed by the MTT assay. The number of viable U87MG cellsand primary cultured glioblastoma cells decreased significantly in aconcentration- and time-dependent manner compared to vehicle control cells. The OD value decreased compared to vehicle control cell.(p<0.05). ButArdipusilloside I did not affect the viability of SVGp12 astrocytes whichpresented the supporting cells that are generously existed in brain parenchyma.The OD value did not alter compared with vehicle control cell(p>0.05).
The biologic security of ardipusilloside I which is promising to be applied inthe clinical management for glioblastoma as a novel chemotherapeutic agent has beenapproved. Moreover, we investigated the role of FasL/Fas signaling mediateddeath receptor pathway in the chemotherapeutic effect of ardipusilloside I in vitro,which suggested an experimental base for developing targeting gene therapeuticagent that aims at specific effector factors. It is warranted that developingassistant agents for ardipusilloside I will consummate its clinical application.
引文
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