ACS Omega, Год журнала: 2024, Номер 9(50), С. 49925 - 49934

Опубликована: Дек. 2, 2024

Targeting nonapoptotic cell death offers a promising strategy for overcoming apoptosis resistance in cancer. In this study, we developed Tat-Ram13, 25-mer peptide that fuses the NOTCH1 intracellular domain fragment RAM13 with cell-penetrating HIV-1 TAT, treatment of T-cell acute lymphoblastic leukemia aberrant mutation. Tat-Ram13 significantly downregulated NOTCH1-target genes T-ALL lines. Furthermore, had potent cytotoxic effects on various human and lymphoma However, it did not affect normal lymphocytes monocytes, some subsets cells, or adherent tumor cells. This cell-selective activity was closely correlated uptake via macropinocytosis triggered rapid death. involved mitochondrial membrane depolarization extracellular release lactate dehydrogenase high-mobility group box-1 protein without activation caspase-3 cleavage PARP-1. These results suggest is mediated by plasma rupture. Moreover, alanine scanning analysis identified four critical hydrophobic amino acids essential its cytotoxicity. Consequently, these tumor-selective, death-inducing agent treating refractory lymphomas resistance.

Язык: Английский