国内团队:纳米颗粒敏化Apo2L/ TRAIL耐药大肠癌患者
创作:Lexi 审核:Lexi 01月13日
  • 开发一个基于氧化铁簇的纳米平台,提高TRAIL/Apo2L或化疗在结直肠癌(CRC)中的疗效;
  • 该纳米颗粒(NanoTRAIL)产生ROS-触发的JNK激活,并诱导随后的自噬辅助DR5上调,导致TRAIL/Apo2L抗肿瘤疗效显著增强;
  • 小鼠皮下CRC移植瘤模型中,与对照组相比,NanoTRAIL显著抑制肿瘤生长、延长生存期,且无明显不良反应;
  • CRC患者来源移植瘤(PDX)模型中,NanoTRAIL治疗显著增强ROS-依赖的自噬辅助DR5上调和肿瘤坏死,提高存活率。
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Lexi
目前结直肠癌(CRC)治疗的一个主要问题是对化疗的反应不足,主要归因于CRC发展过程中肿瘤来源的失调和对正常凋亡通路的逃避。因此,重建肿瘤细胞凋亡通路是治疗CRC的一项重要新兴策略。TRAIL/Apo2L可通过促凋亡受体DR4和DR5诱导肿瘤选择性和p53不依赖的凋亡,其绕过内源性凋亡,直接激活外源性凋亡通路,在临床上备受期待。尽管TRAIL/Apo2L单药治疗在临床前研究中显示了令人鼓舞的结果,但一些靶向TRAIL/Apo2L受体的候选生物药在临床试验中未能达到其主要终点。主要障碍之一是TRAIL/Apo2L的获得性耐药,其机制是多方面的,包括DR4/DR5和caspase-8表达下调。来自厦门大学的刘刚研究团队近日在Biomaterials发表最新研究,开发了一种基于FDA批准的氧化铁纳米颗粒NanoTRAIL,可通过产生ROS-触发的JNK激活,并诱导随后的自噬辅助DR5上调,敏化Apo2L/ TRAIL耐药患者,提高TRAIL/Apo2L在CRC中的疗效,或可应用于临床治疗。
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Biomaterials [IF:10.317]

Oxidative stress-driven DR5 upregulation restores TRAIL/Apo2L sensitivity induced by iron oxide nanoparticles in colorectal cancer

结直肠癌中氧化应激驱动的DR5上调可恢复氧化铁纳米颗粒诱导的TRAIL/Apo2L敏感性

10.1016/j.biomaterials.2019.119753

2019-12-31, Article

Abstract & Authors:展开

Abstract:收起
There exists an emergency clinical demand to overcome TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) resistance, which is a major obstacle attributed to insufficient level or mutation of TRAIL receptors. Here, we developed an iron oxide cluster-based nanoplatforms for both sensitization and MR image-guided evaluation to improve TRAIL/Apo2L efficacy in colorectal cancer, which has an inadequate response to TRAIL/Apo2L or chemotherapy. Specifically, NanoTRAIL (TRAIL/Apo2L-iron oxide nanoparticles) generated ROS (reactive oxygen species)-triggered JNK (c-Jun N-terminal kinase) activation and induced subsequent autophagy-assisted DR5 upregulation, resulting in a significant enhanced antitumor efficacy of TRAIL/Apo2L, which confirmed in both TRAIL-resistant HT-29, intermediately resistant SW-480 and sensitive HCT-116 cells. Furthermore, in a subcutaneous colorectal cancer mouse model, the in vivo tumor retention of NanoTRAIL can be demonstrated by MR T2 weighted contrast imaging, and NanoTRAIL significantly suppressed tumor growth and prolonged the survival time without observable adverse effects compared with control and TRAIL/Apo2L monotherapy. Importantly, in the study of colorectal cancer patient-derived xenograft models, we found that the NanoTRAIL treatment could significantly improve the survival outcome with consistent ROS-dependent autophagy-assisted DR5 upregulation and tumor apoptosis. Our results describe a transformative design that can be applied clinically to sensitize Apo2L/TRAIL-resistant patients using FDA-approved iron oxide nanoparticles.

First Authors:
Yesi Shi

Correspondence Authors:
Gang Liu

All Authors:
Yesi Shi,Junqing Wang,Jingyi Liu,Gan Lin,Fengfei Xie,Xin Pang,Yihua Pei,Yi Cheng,Yang Zhang,Zhongning Lin,Zhengyu Yin,Xiaomin Wang,Gang Niu,Xiaoyuan Chen,Gang Liu

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