Work

Unveiling the link between NADPH oxidase 2 activation and mitochondrial superoxide formation in leukemic cell killing induced by arsenic trioxide

Year: 2024

Type: article

Abstract: This study focused on the interplay between NADPH oxidase 2 (NOX 2) activation and mitochondrial superoxide (mitoO 2 .- ) formation induced by clinically relevant concentrations of arsenic trioxide (ATO; As 2 O 3 ) in acute promyelocytic leukemia (APL) cells. Carefully controlled inhibitor studies and small interfering RNA mediated downregulation of p47 phox (a component of the NOX 2 complex) expression demonstrated that, in an APL cell line, ATO promotes upstream NOX 2 activation critically connected with the formation of mitoO 2 .- and with the ensuing mitochondrial permeability transition (MPT)-dependent apoptosis. Instead, acute myeloid leukemia (AML) cell lines respond to ATO with low NOX 2 activation, resulting in a state that is non-permissive for mitoO 2 .- formation. Consistently, through rescue experiments, we demonstrate that pharmacological stimulation of NOX 2 overcomes resistance in these cells, thereby initiating the same cascade of downstream events observed in APL cells. As a final note, several lines of evidence, including measurement of glutathione , catalase and glutathione peroxidase levels, indicated that the antioxidant machinery was similar in APL and AML cells. The results regarding nuclear factor erythroid 2 p45-related factor 2-dependent antioxidant responses were instead of more complex interpretation as NB4 cells appeared particularly responsive to ATO. Our findings allow a novel interpretation of the interplay between NOX 2 activation and mitoO 2 .- formation induced by ATO, ultimately steering leukemic cells towards MPT-dependent apoptosis. These mechanistic insights provide a rationale for the disparate responses of APL and AML cells to ATO, offering potential avenues for the development of therapeutic intervention tailored to specific leukemia subtypes.

Source: Pharmacological Research

DOI: 10.1016/j.phrs.2024.107554

Authors: Andrea Spina, Andrea Guidarelli, Gloria Buffi, Mara Fiorani, Orazio Cantoni

Institution: University of Urbino

Language: English

Topic: Cell death mechanisms and regulation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,740