Acquisition of a high-mesenchymal cell state by human tumors and cancer cell lines leads to increased cellular plasticity and may contribute to development of cancer drug resistance and tumor recurrence. Although cell plasticity is generally believed to be a protective mechanism for cancer cells, we have discovered that this may also be an exploitable vulnerability. We discovered that cancers that express high levels of ZEB1, a transcription factor that drives the dedifferentiation program known as epithelial-mesenchymal transition (EMT) and is associated with poor prognosis in many tumor types, also generate high levels of hydrogen peroxide (H2O2), which can be exploited as a trigger for release of cancer therapeutics. In the presence of oxidizing agents like H2O2, silver nanoparticles (AgNPs) dissolve to release Ag+. Therefore, we investigated a controlled release mechanism whereby elevated baseline levels of H2O2 in ZEB1high cells leads to dissolution of AgNPs to release Ag+, which then causes cell death. We quantified endogenous levels of H2O2 and sensitivity to AgNP exposure in a panel of ZEB1high and ZEB1low breast cancer cells and found that ZEB1high cancer cells generated significantly more H2O2 and were 5-10 fold more sensitive to AgNPs than ZEB1low cells. By transmission electron microscopy, we observed substantial degradation of AgNPs in endosomes of ZEB1high, MDAMB231 cells but no degradation of AgNPs in Zeb1low non-cancerous MCF-10A cells. AgNP exposure had no effect on cellular redox balance, endoplasmic reticulum stress, DNA damage, and mammary cell polarity in non-cancerous breast epithelial cells, but caused significant damage and apoptosis in ZEB1high breast cancer cells. We found also that ovarian, lung, colorectal, and prostate cancer cell lines exhibiting the ZEB1high mRNA profile were 5 to 500 fold more sensitive to AgNP exposure compared to cancers that came from the same tissue but had a ZEB1low mRNA profile. Intravenous injection of AgNPs significantly reduced ZEB1high MDA-MB-231 tumor growth in mice. No difference in weight between PBS and AgNP treated mice was observed, nor were overt signs of toxicity noticeable (i.e. hunched posture/immobility, and rapid or shallow breathing). Our discovery that ZEB1 is a biomarker that can predict which cancers are most likely to respond to AgNP therapy increases the possibility of future human clinical trials of AgNPs for treatment of well-selected patients.

Elevated levels of hydrogen peroxide in mesenchymal-like cancer cells can selectively trigger the dissolution of silver nanoparticles

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.