A Novel Indole-Dihydroisoxazole Compound Activates Apoptotic, Mitochondrial and Autophagy-related Responses in Lymphoid and Myeloid Leukemia Cells.

Abstract

Isoxazole-derived compounds possess significant pharmacological properties, particularly in the therapy of hematological malignancies. A prominent example is 5-(1-methyl-1H-indol-3-yl)-3-(4-bromophenyl)-4,5-dihydroisoxazole (DHI1), which has previously been reported to exhibit selective cytotoxic activity toward leukemia cell lines. The present study aims to further elucidate the underlying mechanisms of action of DHI1. Treatment of Jurkat (lymphoid lineage) and HL-60 (myeloid lineage) leukemia cell lines with DHI1 resulted in the induction of apoptosis, accompanied by mitochondrial damage, the release of cytochrome c, a decline in mitochondrial potential, and elevated ROS production. Upon exposure to DHI1, leukemia cells showed increased caspase activity, PARP cleavage, and decreased expression of Bcl-xL and ATM, indicating activation of apoptotic processes. Moreover, DHI1 treatment was associated with reduced phosphorylation of NF-κB and ERK signaling pathways. DHI1 was able to significantly inhibit phosphorylation of both targets even in the presence of concurrent administration with inducers. DHI1 treatment resulted in distinct autophagy-associated responses in Jurkat and HL-60 cells, indicating differences in the cellular response between the two leukemia cell lines. These findings highlight the therapeutic potential of isoxazole-derived compounds, particularly DHI1, warranting further investigation in additional preclinical models. The study provides valuable insights into the molecular mechanisms underlying the antiproliferative effects of DHI1, supporting further studies aimed at clarifying its mechanism of action and therapeutic potential.