@Article{or.2025.062951,
AUTHOR = {BHAVYADHARSHINI ARUN, PRARTHANA GOPINATH, ANUP JHA, NISHTHA TRIPATHI, SYED G DASTAGER, SYED K HASAN},
TITLE = {Nigericin-induced apoptosis in acute myeloid leukemia via mitochondrial dysfunction and oxidative stress},
JOURNAL = {Oncology Research},
VOLUME = {33},
YEAR = {2025},
NUMBER = {8},
PAGES = {2161--2174},
URL = {http://www.techscience.com/or/v33n8/63045},
ISSN = {1555-3906},
ABSTRACT = { <b>Background:</b> Acute Myeloid Leukemia (AML) is a highly aggressive clonal hematological malignancy with limited treatment options. This study aimed to evaluate the therapeutic potential of nigericin, a polyether ionophore derived from <i>Streptomyces</i> DASNCL-29, as a mitochondrial-targeted agent for AML treatment. <b>Methods:</b> Nigericin was isolated from <i>Streptomyces</i> DASNCL-29 and characterized via chromatography and NMR. Its cytotoxicity was tested in MOLM13 (sensitive and venetoclax-resistant) and HL60 (sensitive and cytarabine-resistant) cells using the MTT assay. Mitochondrial dysfunction was assessed by measuring reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), and mitochondrial mass. Apoptosis was evaluated with Annexin V/PI assays and immunoblotting, while proteomic analysis was conducted using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) to identify differentially regulated proteins. <b>Results:</b> Nigericin demonstrated potent cytotoxicity with IC<sub>50</sub> values of 57.02 nM in MOLM13-sensitive, 35.29 nM in MOLM13-resistant, 20.49 nM in HL60-sensitive, and 1.197 nM in HL60-cytarabine-resistant cells. Apoptosis was confirmed by Annexin V/PI staining and caspase-3/PARP cleavage, along with MCL-1 downregulation. Mitochondrial dysfunction was evident from increased ROS, reduced Δψm, and decreased mitochondrial mass. Proteomic profiling identified 264 dysregulated proteins, including a 3.8-fold upregulation of Succinate Dehydrogenase [Ubiquinone] Flavoprotein Subunit A (SDHA). <b>Conclusion:</b> Nigericin induces apoptosis in AML cells by disrupting mitochondrial function and enhancing oxidative stress. Its nanomolar potency highlights the need for further mechanistic studies and <i>in vivo</i> evaluations to explore its potential in AML treatment.},
DOI = {10.32604/or.2025.062951}
}