Biomimetic Sodium Transporters Induce Intracellular Sodium Overload to Activate p53-Mediated Apoptosis and Cell Cycle Arrest in Acute Myeloid Leukemia.

Biomimetic sodium ion transporters may offer a potential basis for the development of novel anticancer strategies. This study evaluated quinoline oxadiazole-based Na+ transporters (M1, M2 and M3) for selective Na+ transport and anti-leukemic effects. M1 and M3 localized to cellular membranes and exhibited exceptional Na+ selectivity, with transport rates of 22.85 ± 1.71 and 17.71 ± 1.24, respectively. They independently induced rapid Na+ influx, leading to a 2- to 3-fold increase in intracellular Na+ concentration within 3-6 hours. In acute myeloid leukemia cell lines (MV4-11 and THP-1), this influx caused mitochondrial depolarization (ΔΨm loss of 38-62%), elevated mitochondrial ROS (3- to 6-fold), DNA damage (increased γ-H2AX foci), and proliferation arrest, while M2 was inactive. TP53 wild-type cells showed approximately 3-fold greater sensitivity (IC50 13-16.2 μM) than TP53 mutant cells (IC50 31.55-49.72 μM). Mechanistically, Na+ overload was associated with activation of the ATM-CHK2-p53 axis, causing G1 arrest and Bcl-2-dependent apoptosis in TP53 wild-type cells, whereas TP53-mutant cells rely on a compensatory eIF2α-phosphorylated-driven stress response that inhibits proliferation. Furthermore, anti-AML activity was confirmed in primary AML patient specimens, with M1 and M3 inducing dose-responsive apoptosis (max 66.14% Annexin V+ cells at 80 μM vs 6.7% baseline, IC50 32.08-94.38 μM, p < 0.001), while sparing normal hematopoietic cells. These findings demonstrate that biomimetic Na+ transporters induce potent and selective anti-AML effects through intracellular Na+ overload, particularly in TP53 wild-type cells.