Multi-targeted DATS prevents tumor progression and promotes apoptosis in ectopic glioblastoma xenografts in SCID mice via HDAC inhibition.
Multi-targeted DATS prevents tumor progression and promotes apoptosis in ectopic glioblastoma xenografts in SCID mice via HDAC inhibition.
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多靶性的DATS通过HDAC抑制作用可防止肿瘤进展并促进SCID小鼠异位胶质母细胞瘤异种移植物的细胞凋亡。
DOI：
10.1007/s11060-013-1165-8
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发表时间：
2013-08
影响因子：
3.9
通讯作者：
Das, Arabinda
中科院分区：
文献类型：
--
作者：
Wallace, Gerald C.;Haar, Catherine P.;Vandergrift, W. Alex, III;Giglio, Pierre;Dixon-Mah, Yaenette N.;Varma, Abhay K.;Ray, Swapan K.;Patel, Sunil J.;Banik, Naren L.;Das, Arabinda
胶质母细胞瘤是最恶性和致命的脑肿瘤，尽管进行了积极的化疗和手术干预，但仍然无法治愈。在临床前模型中探索了很少用于胶质母细胞瘤治疗的新化疗药物，并且一些批准的药物已经达到临床环境。然而，成功率并不高。以前的研究涉及大蒜成分二烯丙基三硫化物（DATS），已表明显着的体外抗癌作用，包括：胶质母细胞瘤生长抑制，外在和内在的凋亡途径激活，和细胞死亡。DATS还显示出抑制组蛋白脱乙酰酶活性并阻止胶质母细胞瘤肿瘤进展。我们假设DATS通过HDAC抑制多种促凋亡途径来阻断异位U87 MG诱导的肿瘤。为此，在SCID小鼠中产生异位肿瘤，随后每天腹膜内注射DATS进行治疗。结果表明，一系列DATS剂量（10μg/kg-10 mg/kg）在7天后剂量依赖性地减少肿瘤体积和肿瘤内有丝分裂细胞的数量。我们的组织学和生物化学测定表明，DATS减少肿瘤中的有丝分裂，降低HDAC活性，增加H3和H4的乙酰化，抑制细胞周期进展，促进凋亡级联激活（m-calpian，Bax，caspase-3），并减少促存活标志物（存活素，Bcl-2，p-Akt，c-Myc，mTOR，EGFR，VEGF）。我们的数据还表明，增加p21/WAF 1的表达，这与增加p53的表达和MDM 2降解后DATS治疗。最后，组织学评估和酶测定表明，即使在本研究中给予最高剂量的DATS也不会对肝功能产生负面影响。这些在体内的研究结果强烈支持原位调查DATS的治疗潜力，并进一步审查其抗癌活性背后的表观遗传机制。
Glioblastoma, the most malignant and lethal of brain tumors, remains incurable despite aggressive chemotherapy and surgical interventions. Few new chemotherapeutics for glioblastoma therapy have been explored in preclinical models, and some agents approved for have reached the clinical setting. However success rates are not significant. Previous investigations involving diallyl trisulfide (DATS), a garlic constituent, have indicated significant anti-cancer effects in vitro, including: glioblastoma growth inhibition, extrinsic and intrinsic apoptotic pathway activation, and cell death. DATS has also been shown to inhibit histone deacetylase activity and impede glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG induced tumors by inhibiting multiple pro-apoptotic pathways via HDAC. To this end, ectopic tumors were developed in SCID mice and subsequently treated with daily intraperitoneal injections of DATS. Results indicate that a range of DATS doses (10μg/kg-10mg/kg) dose-dependently reduced tumor volume and number of mitotic cells within tumors after seven days. Our histological and biochemical assays demonstrate that DATS reduces mitosis in tumors, decreases HDAC activity, increases in acetylation of H3 and H4, inhibits cell cycle progression, promotes apoptotic cascade activation (m-calpian, Bax, caspase-3) and decreases pro-survival markers (Survivin, Bcl-2, p-Akt, c-Myc, mTOR, EGFR, VEGF). Our data also demonstrates an increase in p21/WAF1 expression, which correlates with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and enzyme assays suggest that even the highest dose of DATS administered in this study did not negatively impact hepatic function. These in vivo findings strongly support orthotopic investigation into the therapeutic potential of DATS and further review of the epigenetic mechanisms behind its anti-cancer activities.
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影响因子：
5.7
作者：
Shankar, Sharmila;Chen, Qinghe;Srivastava, Rakesh K.
通讯作者：
Srivastava, Rakesh K.
影响因子：
6.1
作者：
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影响因子：
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作者：
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desBordes, C
DOI：
10.1590/s0100-879x2010000900003
发表时间：
2010-09-01
影响因子：
2.3
作者：
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通讯作者：
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作者：
Karmakar, Surajit;Choudhury, Subhasree Roy;Ray, Swapan K.
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