Exploiting the ferroaddiction of pancreatic cancer cells using Fe-doped nanoparticles

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor survival rates. Here, we evaluated iron-doped hydroxyapatite (FeHA) as a potential nanomedicine-based approach to combat PDAC. FeHA, in combination with a sublethal dose of the glutathione peroxidase 4 (GPX4) inhibitor RSL3, was found to trigger ferroptosis in KRAS mutant PANC-1 cells, but not in BxPC3 cells, while sparing normal human cells (fibroblasts and peripheral blood mononuclear cells). These findings were recapitulated in 3D spheroids generated using PDAC cells harboring wild-type versus mutant KRAS. Moreover, ferroptosis induction by FeHA plus RSL3 was reversed by the knockdown of STEAP3, a metalloreductase responsible for converting Fe3+ to Fe2+. Taken together, our data show that FeHA is capable of triggering cancer cell death in a KRAS-selective, STEAP3-dependent manner in PDAC cells.

Automated summary

In this study, iron-doped hydroxyapatite (FeHA) was evaluated as a potential nanomedicine approach for treating PDAC. The results showed that FeHA, in combination with a sublethal dose of the GPX4 inhibitor RSL3, could trigger ferroptosis in KRAS mutant PANC-1 cells while sparing normal human cells. The induction of ferroptosis by FeHA plus RSL3 was found to be dependent on the metalloreductase STEAP3 in PDAC cells.