Tandem Molecular Self-Assembly Selectively Inhibits Lung Cancer Cells by Inducing Endoplasmic Reticulum Stress
Debin Zheng,
Yumiao Chen,
Sifan Ai,
Renshu Zhang,
Zhengfeng Gao,
Chunhui Liang,
Li Cao,
Yaoxia Chen,
Zhangyong Hong,
Yang Shi,
Ling Wang,
Xingyi Li,
Zhimou Yang
Affiliations
Debin Zheng
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
Yumiao Chen
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
Sifan Ai
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
Renshu Zhang
School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, and Wenzhou Institute of Biomaterials and Engineering, CNITECH, CAS, Wenzhou 325035, China
Zhengfeng Gao
College of Pharmacy, Nankai University, Tianjin 300071, China
Chunhui Liang
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
Li Cao
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
Yaoxia Chen
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
Zhangyong Hong
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
Yang Shi
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
Ling Wang
College of Pharmacy, Nankai University, Tianjin 300071, China
Xingyi Li
School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, and Wenzhou Institute of Biomaterials and Engineering, CNITECH, CAS, Wenzhou 325035, China
Zhimou Yang
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
The selective formation of nanomaterials in cancer cells and tumors holds great promise for cancer diagnostics and therapy. Until now, most strategies rely on a single trigger to control the formation of nanomaterials in situ. The combination of two or more triggers may provide for more sophisticated means of manipulation. In this study, we rationally designed a molecule (Comp. 1) capable of responding to two enzymes, alkaline phosphatase (ALP), and reductase. Since the A549 lung cancer cell line showed elevated levels of extracellular ALP and intracellular reductase, we demonstrated that Comp. 1 responded in a stepwise fashion to those two enzymes and displayed a tandem molecular self-assembly behavior. The selective formation of nanofibers in the mitochondria of the lung cancer cells led to the disruption of the mitochondrial membrane, resulting in an increased level of reactive oxygen species (ROS) and the release of cytochrome C (Cyt C). ROS can react with proteins, resulting in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This severe ER stress led to disruption of the ER, formation of vacuoles, and ultimately, apoptosis of the A549 cells. Therefore, Comp. 1 could selectively inhibit lung cancer cells in vitro and A549 xenograft tumors in vivo. Our study provides a novel strategy for the selective formation of nanomaterials in lung cancer cells, which is powerful and promising for the diagnosis and treatment of lung cancer.
