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Abstract：
Glioblastoma is the most devastating primary brain tumor. Current treatment is palliative, making necessary the development of new therapeutic strategies to offer alternatives to patients. Therefore, endophytes represent an interesting source of natural metabolites with anticancer potential. These microorganisms reside in tissues of living plants and act to improve their growth. Evidence revealed that several medicinal plants are colonized by endophytic fungi producer of antitumor metabolites. Achyrocline satureioides is a Brazilian medicinal plant characterized by its properties against gastrointestinal disturbances, anticancer and antioxidant effects. However, there are no reports describing the endophytic composition of A. satureioides. The present study proposes the isolation of endophytic fungus from A. satureioides, extract preparation, phytochemical characterization and evaluation of its antiglioma potential. Our data showed that crude extracts of endophyte decreased glioma viability with IC50 values of 1.60-1.63 μg/mL to eDCM (dichloromethane extract) and 37.30-55.12 μg/mL to eEtAc (ethyl acetate extract), respectively. Crude extracts induced cell death by apoptosis with modulation of redox status. In order to bioprospect anticancer metabolites, endophytic fungus extracts were subjected to guided fractionation and purification yielded five fractions of each extract. Six of ten fractions showed selective antiproliferative activity against glioma cells, with IC50 values ranged from 0.95 to 131.3 μg/mL. F3DCM (from eDCM) and F3EtAc (from eEtAc) fractions promoted C6 glioma toxicity with IC50 of 1.0 and 27.05 μg/mL, respectively. F3EtAc fraction induced late apoptosis and arrest in G2/M stage, while F3DCM promoted apoptosis with arrest in Sub-G1 phase. Moreover, F3DCM increased antioxidant defense and decreased ROS production. Additionally, F3DCM showed no cytotoxic activity against astrocytes, revealing selective effect. Based on promising potential of F3DCM, we identified the production of Sch-642305, a lactone, which showed antiproliferative properties with IC50 values of 1.1 and 7.6 μg/mL to C6 and U138MG gliomas, respectively. Sch-642305 promoted arrest on cell cycle in G2/M inducing apoptosis. Furthermore, this lactone decreased glioma cell migration and modulated redox status, increasing superoxide dismutase and catalase activities and enhancing sulfhydryl content, consequently suppressing reactive species of oxygen generation. Taken together, these results indicate that metabolites produced by endophytic fungus isolated from A. satureioides have therapeutic potential as antiglioma agent.
摘要：
胶质母细胞瘤是最具破坏性的原发性脑肿瘤。目前的治疗是姑息治疗，必须开发新的治疗策略，为患者提供替代方案。因此,内生菌代表了具有抗癌潜力的天然代谢物的有趣来源。这些微生物驻留在活植物的组织中并起作用以改善其生长。证据表明，几种药用植物被抗肿瘤代谢产物的内生真菌定植。Achyroclinesatureioides是一种巴西药用植物，其特点是具有抗胃肠道紊乱的特性。抗癌和抗氧化作用。然而,没有报道描述沙丁香的内生成分。本研究提出了从A.satureioides分离内生真菌，提取物制备,植物化学表征及其抗胶质瘤潜力的评估。我们的数据表明，内生菌的粗提物降低了神经胶质瘤的活力，对eDCM（二氯甲烷提取物）的IC50值为1.60-1.63μg/mL，对eEtAc（乙酸乙酯提取物）的IC50值为37.30-55.12μg/mL，分别。粗提物通过调节氧化还原状态通过凋亡诱导细胞死亡。为了生物前景抗癌代谢物，对内生真菌提取物进行指导分馏和纯化，得到每种提取物的五个级分。十个部分中有六个显示出对神经胶质瘤细胞的选择性抗增殖活性，IC50值范围为0.95至131.3μg/mL。F3DCM（来自eDCM）和F3EtAc（来自eEtAc）部分促进C6神经胶质瘤毒性，IC50为1.0和27.05μg/mL，分别。F3EtAc分数诱导晚期细胞凋亡并阻滞于G2/M期，而F3DCM在Sub-G1期抑制促进细胞凋亡。此外，F3DCM增加了抗氧化防御并减少了ROS的产生。此外,F3DCM对星形胶质细胞无细胞毒活性,显示选择性效应。基于F3DCM的潜力，我们确定了Sch-642305，一种内酯，对C6和U138MG胶质瘤显示出抗增殖特性，IC50值为1.1和7.6μg/mL，分别。Sch-642305促进G2/M期细胞周期阻滞诱导细胞凋亡。此外，这种内酯减少神经胶质瘤细胞迁移和调节氧化还原状态，增加超氧化物歧化酶和过氧化氢酶活性，提高巯基含量，因此抑制了氧气产生的反应性物质。一起来看,这些结果表明，由分离自a.satureioides的内生真菌产生的代谢产物具有作为抗神经胶质瘤药物的治疗潜力。
