Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA.
Department of Neurological Surgery, Ohio State University Wexner Medical College, Columbus, OH, USA.
Cancer Chemother Pharmacol. 2018 Dec;82(6):945-952. doi: 10.1007/s00280-018-3684-7. Epub 2018 Sep 12.
PURPOSE/INTRODUCTION: Glioblastoma (GB) remains incurable despite aggressive chemotherapy, radiotherapy, and surgical interventions; immunotherapies remain experimental in clinical practice. Relevant preclinical models that can accurately predict tumor response to therapy are equally challenging. This study aimed to validate the effect of the naturally occurring agent diallyl trisulfide (DATS) in human GB in relevant pre-clinical models.
Ex vivo slice culture, in vivo cell line derived orthotopic xenograft and patient-derived orthotopic xenograft (PDX) animal models of GB were utilized to assess efficacy of treatment with DATS.
Our results showed 72-h treatments of 25 µM DATS induced cell death in ex vivo human GB slice culture. We treated U87MG orthotopic xenograft models (U87MGOX) and patient-derived orthotopic xenograft models (PDX) with daily intraperitoneal injections of DATS for 14 days. Magnetic resonance (MR) imaging of mice treated with DATS (10 mg/kg) demonstrated reduced tumor size at 5 weeks when compared with saline-treated U87MGOX and PDX controls. Hematoxylin (H&E) staining demonstrated dose-dependent reduction in gross tumor volume with decreased proliferation and decreased angiogenesis. Western blotting showed that DATS was associated with increases in histone acetylation (Ac-Histone H3/H4) and activated caspase-3 in this novel preclinical model. Histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function.
DATS may be an effective and well-tolerated therapeutic agent in preventing tumor progression and inducing apoptosis in human GB.
目的/引言：尽管采用了积极的化疗、放疗和手术干预，胶质母细胞瘤（GB）仍然无法治愈；免疫疗法在临床实践中仍然是实验性的。同样具有挑战性的是，能够准确预测肿瘤对治疗反应的相关临床前模型。本研究旨在验证天然存在的二烯丙基三硫化物（DATS）在相关临床前模型中对人 GB 的治疗效果。
利用离体脑片培养、体内细胞系衍生的原位异种移植和患者来源的原位异种移植（PDX）GB 动物模型来评估 DATS 治疗的疗效。
我们的结果表明，25µM DATS 的 72 小时治疗可诱导离体人脑 GB 切片培养中的细胞死亡。我们用 DATS 每日腹腔注射治疗 U87MG 原位异种移植模型（U87MGOX）和患者来源的原位异种移植模型（PDX）14 天。与生理盐水处理的 U87MGOX 和 PDX 对照相比，用 DATS（10mg/kg）处理的小鼠的磁共振（MR）成像显示在 5 周时肿瘤体积缩小。苏木精（H&E）染色显示，与对照组相比，总肿瘤体积有剂量依赖性减小，增殖减少，血管生成减少。Western blot 显示，在这个新的临床前模型中，DATS 与组蛋白乙酰化（Ac-Histone H3/H4）的增加和激活的 caspase-3 有关。组织学评估和酶测定表明，即使是 DATS 的最高剂量也不会对肝功能产生负面影响。
DATS 可能是一种有效且耐受性良好的治疗剂，可预防人 GB 中的肿瘤进展并诱导细胞凋亡。
