3-Hydroxyquinazoline Derivatives, Analogues of Erastin, Induce Ferroptosis in Colorectal Cancer Cells

Objective: In recent years, significant progress has been achieved in the treatment of patients with colorectal cancer, but in most cases, treatment is accompanied by the development of drug resistance. Recently discovered iron-dependent cell death, ferroptosis, provides promising therapeutic targets that might aid in reducing the recurrence rates. Methods: Derivatives of 3-hydroxyquinazoline were obtained by chemical synthesis and have a purity of at least 95%. In this study 2D cultivation of HCT-116 and DLD-1 cells, phase-contrast, and fluorescence microscopy were used. The ferroptotic cell death was identified by the level of lipid peroxidation using fluorescent indicator C11-BODIPY. Results and Discussion: We have examined the effect of 3-hydoxyquinazoline derivatives on ferroptosis induction in two colorectal cancer cell lines, HCT-116 and DLD-1. The level of lipid peroxidation in HCT-116 cells induced by some compounds approached the activity of the reference drug erastin. This scenario changed significantly when the ferroptosis induction was studied in DLD-1 cells. Fluorescence intensity induced by two 3-hydroxyquinazoline derivatives in DLD-1 cells exceeded those of erastin. Conclusions: The preliminary results suggest that three new compounds can be considered as antitumor agents for the treatment of colorectal cancer, particularly for the tumors with a highly malignant phenotype. The data obtained also indicate the prospects of further searching for ferroptosis inducers among 3-hydroxyquinazoline derivatives.