PO-485 Ferroptosis is the nexus for zero-valent iron-based highly selective anticancer nanotherapy and anti-nanoresistance

• Published in: ESMO open Vol. 3; no. Suppl 2; p. A212
• Main Authors: Huang, KJ, Wu, SR, Shieh, DB
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.07.2018
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1136/esmoopen-2018-EACR25.503

IntroductionResistance of cancer cells to bare nanomaterials is rarely discussed but critical for clinical success in nanomedicine. Insight to the nanoresistance mechanism can optimise precision nanomedicine. Here, we report that ferroptosis is the battlefield between zero-valent iron nanoparticles (ZVI NPs) and cancer cells, which dominants therapeutic efficacy and development of resistance. Accumulating mitochondrial lipid peroxidation (LPO) and attenuation of glutathione peroxidase (GPx) are the hallmarkers for ZVI-induced ferroptosis. Although refractory cancer cells can defense above challenges, ferroptosis inducers (FINs) can sensitise them without affecting normal cells. Our findings suggest that ferroptosis pathway may provide druggable targets to reverse resistance for ZVI-based nanomedicine.Material and methodsPreparation of ZVI NPsCell survival assaySubcellular ROS analysisAssessing mitochondrial functionsLive-cell imagingWestern blot of subcellular fractionTranscriptome analysisXenograft modelResults and discussionsOral cancer cells exhibit distinct sensitivity to ZVI NPs. In the sensitive cells, the core mechanism of ZVI-cytotoxicity is ferroptosis and it is different from FINs-induced ferroptosis. It is caused by mitochondrial LPO and is followed by loss of mitochondrial function. In addition, GPx proteins were declined in subcellular organelles after ZVI NPs treatment. In contrast, ZVI-refractory cells were able to maintain GPx. They harboured higher ROS-scavenging capacity and higher mitochondrial activity to escape from crisis. The transcriptome of paired ZVI-sensitive/refractory clones showed some routes may participate the ZVI-resistance such as NADPH supply, ROS-detoxification, and PUFA metabolism. Finally, we confirmed that integrating FINs with ZVI NPs could revert resistant cancers to be treatable while still sparing normal cells in vitro and in vivo.ConclusionThe ferroptosis mechanism governing the selective ZVI-cytotoxicity toward cancer cells and their links to nanoresistance were reported for the first time. Our results suggest that ferroptosis is the nexus for ZVI-based anticancer nanotherapy and its resistance development. Detection and modulation of ferroptosis-susceptibility not only provide a biomarker-based nanomedicine, but also open a novel gateway to improve clinical outcome by management of nanoresistance. We anticipate these findings will inspire new concepts in NPs-induced ferroptosis, NPs-resistance, and anti-resistance strategy for precision nanomedicine.