A Potent Nano-chemotherapy Strategy by Exploiting the Acquired Vulnerability of Cisplatin-resistant Tumors
A research team led by Prof. LIANG XingJie from the National Center for Nanoscience and Technology (NCNST) of the Chinese Academy of Sciences (CAS), collaborating with Profs. GUO Weisheng from Guangzhou Medical University and CHANG Jin from Tianjin University reported a new strategy of nano-chemotherapy to cisplatin-resistant tumor by exploiting the acquired intracellular hypoxia of cancer cells. This work was recently published in Science Advances.
Platinum anticancer drugs have been widely used in standard-of-care chemotherapy for many types of cancer. However, most patients almost invariably relapse with resistant lesions that is frequently caused by substantial DNA repair. Inhibition of DNA repair by targeted drugs is a pivotal approach to potentiating the therapeutic efficacy of cisplatin, but adaptive drug resistance is still mostly inevitable and frequently caused by activation of other alternative pathways. Therefore, finding and exploiting the inevitable weakness in drug-resistant cancer cells is expected to explore an inspired strategy to combat tumor resistance.
In this work, the researchers constructed multiple cisplatin-resistant tumor cell lines by simulating the occurrence of cisplatin resistance in clinical tumors. They found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia indicating that the intracellular environment is more hypoxic in the cisplatin-resistant cells. Inspired by this finding, the researchers proposed an inspired nano-chemotherapy new therapy strategy by exploiting the acquired weakness of cisplatin-resistant tumors via increasing intracellular hypoxia. The researchers constructed a liposomal nanomedicine (denoted as HYDRI NM), which is loaded with glucose oxidase, hypoxia-activatable tirapazamine (TPZ) and a platinum (IV) prodrug. The nanomedicine not only uses but also actively aggravates the intracellular hypoxia characteristics of cisplatin-resistant tumors, thereby effectively activating TPZ. cytotoxicity. The active TPZ not only exhibits strong anti-tumor activity, but also effectively down-regulation of xeroderma pigmentosum group F (XPF), an overexpressed DNA self-repairing protein that causes acquired resistance of cancer cells to cisplatin, thereby achieving a synergistically enhanced anti-tumor effect with platinum prodrugs. In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here.
This work was financially supported by the National Natural Science Foundation of China (NSFC) key projects, NSFC international collaboration key project, NSFC-German Research Foundation (DFG) project et al.
Fig. Schematic illustration of the structure of the HYDRI NMs and hypoxia-induced reversal of cisplatin resistance.