2. Academic Validation
  3. Oxidative stress-driven DR5 upregulation restores TRAIL/Apo2L sensitivity induced by iron oxide nanoparticles in colorectal cancer

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

  • Biomaterials. 2020 Mar;233:119753. doi: 10.1016/j.biomaterials.2019.119753.
Yesi Shi 1,  Junqing Wang 2,  Jingyi Liu 3,  Gan Lin 1,  Fengfei Xie 1,  Xin Pang 1,  Yihua Pei 4,  Yi Cheng 1,  Yang Zhang 1,  Zhongning Lin 1,  Zhengyu Yin 4,  Xiaomin Wang 4,  Gang Niu 5,  Xiaoyuan Chen 5,  Gang Liu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China.
  • 2 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
  • 3 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China; School of Medicine, Xiamen University, Xiamen, 361105, China.
  • 4 School of Medicine, Xiamen University, Xiamen, 361105, China; Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, 361004, China.
  • 5 Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, 20892, USA.
  • 6 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, 361102, China. Electronic address: [email protected].
PMID: 31923762 DOI: 10.1016/j.biomaterials.2019.119753
Abstract

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 nanoplatform 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.

Keywords

Autophagy; Colorectal cancer; DR5; Iron oxide nanoparticle; ROS; TRAIL/Apo2L.

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