Open Access

ARTICLE

Nigericin-induced apoptosis in acute myeloid leukemia via mitochondrial dysfunction and oxidative stress

BHAVYADHARSHINI ARUN^1,#, PRARTHANA GOPINATH^1,2,#, ANUP JHA^1,3, NISHTHA TRIPATHI¹, SYED G DASTAGER^4,*, SYED K HASAN^1,3,*

1 Hasan Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi, Mumbai, 410210, India
2 Department of Biotechnology, Indian Institute of Technology Madras (IIT Madras), Chennai, 600036, India
3 Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, 400094, India
4 National Collection of Industrial Microorganisms (NCIM), CSIR National Chemical Laboratory, Pune, 411008, India

* Corresponding Authors: SYED G DASTAGER. Email: ; SYED K HASAN. Email:
# Joint first author

Oncology Research 2025, 33(8), 2161-2174. https://doi.org/10.32604/or.2025.062951

Received 31 December 2024; Accepted 19 May 2025; Issue published 18 July 2025

Abstract

Background: 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 Streptomyces DASNCL-29, as a mitochondrial-targeted agent for AML treatment. Methods: Nigericin was isolated from Streptomyces 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. Results: Nigericin demonstrated potent cytotoxicity with IC₅₀ 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). Conclusion: 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 in vivo evaluations to explore its potential in AML treatment.

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