Melanoma is a highly aggressive cancer derived from the melanocytic lineage that is difficult to treat once metastasis occurs, with a 5-year overall survival for stage IV disease of 25 – 50%. The use of proferritin for cancer treatment has generated great enthusiasm and stimulated broader research efforts in the field.
Despite the high focus of iron death studies and lipid peroxidation in cancer, published reports assessing lipid peroxidation in cancer use indirect, nonspecific protocols. Lack of LC-MS studies of oxidatively modified lipids in cancer cells undergoing iron death.
Researchers from the University of Pittsburgh are at Redox Biol. Published "Redox phospholipidomics discovers pro-ferroptotic death signals in A375 melanoma cells in vitro and in vivo", the study revealed that LC-MS / MS-based redox lipidomics is a sensitive and precise method for detecting and characterizing phospholipid biomarkers of iron deposition in radiation-and chemotherapy-induced cancer cells.
Growing cancer cells effectively avoid most of the regulated cell death programs, especially apoptosis. This requires the search for alternative treatments to cause cancer cell death, one of which is iron death. One of the barriers to cancer treatment using ferritin precursor drugs is the lack of adequate biomarkers of ferritin deposition. Deiron is accompanied by peroxidation of the polyunsaturated phosphatidylethanolamine (PE) to hydrogen peroxide (-OOH) derivatives, which is a death signal.
In this study, the investigators demonstrated that in vitro RSL 3-induced A375 melanoma cell death can be fully prevented by ferrirestin-1, indicating their high sensitivity to iron death. Treatment of A375 cells with RSL 3 resulted in significant accumulation of the biomarkers of iron death PE- (18:0 / 20:4-OOH) and PE- (18 / 0 / 22:4-OOH, and the oxidative truncation-PE- (18:0 / hydroxyl-8-oxygen-oct-6-enic acid (HOOA) and PC- (18:0 / HOOA).
Significant inhibition of RSL 3 on melanoma growth was observed in vivo. Redox phospholiomics showed increased 18:0 / 20:4-OOH levels in the RSL 3 treated group compared with the control group. Furthermore, the PE- (18:0 / 20:4-OOH) species were identified as the major contributors to the separation of the control and RSL 3 treatment groups, with the highest variable importance in the prediction scores. Pearson's correlation analysis showed a correlation between tumor weight and PE- (18:0 / 20:4-OOH), PE-18:0 / HOOA, and PE16:0-HOOA content.
In conclusion, aggressive pro-ferritin targeting of cancer cells combined with precise and reliable antiferriin targets for regulatory and effector immune cells is a novel optimization and balanced differential approach.
