Copper-Based Metal-Organic Framework Overcomes Cancer Chemoresistance through Systemically Disrupting Dynamically Balanced Cellular Redox Homeostasis.
Jia LiuYe YuanYanni ChengDaan FuZhongyin ChenYang WangLifang ZhangChundong YaoLin ShiMingyi LiCheng ZhouMeizhen ZouGuobin WangLin WangZheng WangPublished in: Journal of the American Chemical Society (2022)
Chemodrug resistance is a major reason accounting for tumor recurrence. Given the mechanistic complexity of chemodrug resistance, molecular inhibitors and targeting drugs often fail to eliminate drug-resistant cancer cells, and sometimes even promote chemoresistance by activating alternative pathways. Here, by exploiting biochemical fragility of high-level but dynamically balanced cellular redox homeostasis in drug-resistant cancer cells, we design a nanosized copper/catechol-based metal-organic framework (CuHPT) that effectively disturbs this homeostasis tilting the balance toward oxidative stress. Within drug-resistant cells, CuHPT starts disassembly that is triggered by persistent consumption of cellular glutathione (GSH). CuHPT disassembly simultaneously releases two structural elements: catechol ligands and reductive copper ions (Cu + ). Both of them cooperatively function to amplify the production of intracellular radical oxidative species (ROS) via auto-oxidation and Fenton-like reactions through exhausting GSH. By drastically heightening cellular oxidative stress, CuHPT exhibits selective and potent cytotoxicity to multiple drug-resistant cancer cells. Importantly, CuHPT effectively inhibits in vivo drug-resistant tumor growth and doubles the survival time of tumor-bearing mice. Thus, along with CuHPT's good biocompatibility, our biochemical, cell biological, preclinical animal model data provide compelling evidence supporting the notion that this copper-based MOF is a predesigned smart therapeutic against drug-resistant cancers through precisely deconstructing their redox homeostasis.
Keyphrases
- drug resistant
- metal organic framework
- multidrug resistant
- acinetobacter baumannii
- oxidative stress
- induced apoptosis
- dna damage
- oxide nanoparticles
- hydrogen peroxide
- cell therapy
- type diabetes
- cell death
- wastewater treatment
- stem cells
- mesenchymal stem cells
- endoplasmic reticulum stress
- diabetic rats
- ischemia reperfusion injury
- fluorescent probe
- machine learning
- skeletal muscle
- young adults
- big data
- adipose tissue
- bone marrow
- deep learning
- data analysis
- squamous cell
- drug induced
- hip fracture