A hypoxia- and telomerase-responsive oncolytic adenovirus expressing secretable trimeric TRAIL triggers tumour-specific apoptosis and promotes viral dispersion in TRAIL-resistant glioblastoma.
A hypoxia- and telomerase-responsive oncolytic adenovirus expressing secretable trimeric TRAIL triggers tumour-specific apoptosis and promotes viral dispersion in TRAIL-resistant glioblastoma.
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表达可分泌的三聚体trigg的低氧和端粒酶反应性肿瘤腺病毒会触发肿瘤特异性细胞凋亡，并促进耐痕量的胶质母细胞瘤中的病毒分散体。
DOI：
10.1038/s41598-018-19300-6
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发表时间：
2018-01-23
影响因子：
4.6
通讯作者：
Yun CO
中科院分区：
文献类型：
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作者：
Oh E;Hong J;Kwon OJ;Yun CO
胶质母细胞瘤是一种高度侵袭性的恶性肿瘤，具有细胞凋亡抵抗性，传统的癌症治疗方法难以治愈。在这方面，一种选择性靶向肿瘤组织并诱导肿瘤细胞裂解的溶瘤腺病毒是一种很有前途的治疗选择。我们设计并构建了一个缺氧反应和癌症特异性修饰的人类端粒酶逆转录酶（H5CmTERT）启动子来驱动溶瘤腺病毒（H5CmTERT- ad）的复制。为了增强H5CmTERT-Ad对恶性胶质母细胞瘤的抗肿瘤作用，我们还生成了表达可分泌的三聚体肿瘤坏死因子相关凋亡诱导配体（H5CmTERT-Ad/TRAIL）的H5CmTERT-Ad。与在内源性腺病毒启动子控制下复制的同源对照溶瘤腺病毒相比，H5CmTERT启动子调控的溶瘤腺病毒显示出癌症特异性和优越的细胞杀伤作用。在缺氧条件下，H5CmTERT-Ad和H5CmTERT-Ad/TRAIL的癌细胞杀伤作用明显高于正常缺氧条件下，这是由于启动子的缺氧反应性。H5CmTERT-Ad/TRAIL在TRAIL耐药的皮下和原位胶质母细胞瘤异种移植模型中表现出比H5CmTERT-Ad更强的抗肿瘤效果，这是通过诱导细胞凋亡和在肿瘤组织中更广泛的病毒分布来实现的。总之，我们的研究结果表明，H5CmTERT-Ad/TRAIL可以通过在TRAIL高度耐药的胶质母细胞瘤中诱导细胞凋亡来促进溶瘤腺病毒的扩散。
Glioblastoma is a highly aggressive and malignant type of cancer that is apoptosis resistant and difficult to cure by conventional cancer therapies. In this regard, an oncolytic adenovirus that selectively targets the tumour tissue and induces tumour cell lysis is a promising treatment option. We designed and constructed a hypoxia-responsive and cancer-specific modified human telomerase reverse transcriptase (H5CmTERT) promoter to drive replication of an oncolytic adenovirus (H5CmTERT-Ad). To enhance the anti-tumour efficacy of H5CmTERT-Ad against malignant glioblastoma, we also generated an H5CmTERT-Ad expressing secretable trimeric tumour necrosis factor-related apoptosis-inducing ligand (H5CmTERT-Ad/TRAIL). H5CmTERT promoter-regulated oncolytic adenoviruses showed cancer-specific and superior cell-killing effect in contrast to a cognate control oncolytic adenovirus replicating under the control of the endogenous adenovirus promoter. The cancer cell-killing effects of H5CmTERT-Ad and H5CmTERT-Ad/TRAIL were markedly higher during hypoxia than normoxia owing to hypoxia responsiveness of the promoter. H5CmTERT-Ad/TRAIL showed more potent anti-tumour efficacy than H5CmTERT-Ad did in a xenograft model of TRAIL-resistant subcutaneous and orthotopic glioblastoma through superior induction of apoptosis and more extensive virus distribution in the tumour tissue. Altogether, our findings show that H5CmTERT-Ad/TRAIL can promote dispersion of an oncolytic adenovirus through robust induction of apoptosis in a highly TRAIL-resistant glioblastoma.
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影响因子：
3.7
作者：
Jeong, Moonsup;Kwon, Yong-Sam;Park, Soon-Hye;Kim, Chae-Young;Jeun, Sin-Soo;Song, Kang-Won;Ko, Yong;Robbins, Paul D.;Billiar, Timothy R.;Kim, Byong-Moon;Seol, Dai-Wu
通讯作者：
Seol, Dai-Wu
影响因子：
2.8
作者：
AUMULLER, G;SEITZ, J;SCHEIT, KH
通讯作者：
SCHEIT, KH
影响因子：
15.9
作者：
Baldwin, AS
通讯作者：
Baldwin, AS
影响因子：
5.1
作者：
Binley, K;Askham, Z;Naylor, S
通讯作者：
Naylor, S
影响因子：
--
作者：
Herms, JW;von Loewenich, FD;Kretzschmar, HA
通讯作者：
Kretzschmar, HA