Noncanonical inhibition of topoisomerase II alpha by oxidative stress metabolites

Redox Biology, Год журнала: 2025, Номер unknown, С. 103504 - 103504

Опубликована: Янв. 1, 2025

During its catalytic cycle, the homodimeric ATPase topoisomerase II alpha (TOP2A) cleaves double stranded DNA and remains covalently bound to 5' ends via tyrosine phosphodiester bonds. After passing a second, intact duplex through, TOP2A rejoins break releases from DNA. Thereby, can relieve strain accumulated during transcription, replication chromatin remodeling disentangle sister chromatids for mitosis. Chemotherapy agents such as etoposide are poisons that trap mid-cycle, cleaved DNA, leaving behind strand breaks activating damage response. While has been proposed stabilize TOP2A-DNA cleavage complex (TOP2Acc) interfacial inhibition, we have elucidated complementary mechanism mediated by ability of other induce oxidative stress. Consequently, lipid peroxidation accumulation lipid-derived electrophiles 4-hydroxynonenal (HNE) results in covalent modification TOP2A, both blocking activity trapping TOP2Acc. HNE modifies multiple sites on human vitro, including alkylating Cys216 domain DNA-dependent fashion. Taken together, our data suggest an underappreciated role redox sensor tumor cells, connecting stress signaling thereby creating target redox-active drugs.

Язык: Английский

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The chemotherapy agent doxorubicin induces CNS expression of Ascl1, a regulator of adult neurogenesis and differentiation

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 21, 2025

Cancer-related cognitive impairment (CRCI) is a common side effect of cancer and its treatments. Cancer chemotherapy has been associated with hippocampal dysfunction memory impairment. We investigated the effects one agent, doxorubicin, on transcription factor Ascl1 proliferation stem cells in brain. used an inducible mouse model designed to express TdTomato Ascl1-lineage cells. Five six-month-old Ascl1-CreERT2:ROSA mice were treated peripherally single dose either doxorubicin (10 mg/kg) or DMSO control (n = 9 per group, n 4–5 sex). analyzed brains that had exposed for 2 weeks induced expression after first week. immunostaining neurogenesis stage specific markers evaluate neuronal differentiation dentate gyrus hippocampus. Overall, significantly increased by 81% at this time point. As measured double stains Sox2, GFAP, NeuroD1, doxorubicin-treated experienced increase Ascl1-mediated neural compared control. A similar significant number Ascl1-expressing (by 146%) treatment was observed gray matter cerebral cortex. Thus, rather than leading loss developing neurons, we found their appearance progression, suggesting losses from chemotherapies may require greater more sustained damage.

Язык: Английский

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Neurotoxicity of the antineoplastic drugs: “Doxorubicin” as an example

Journal of Molecular Histology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Язык: Английский

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Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role?

Life Sciences, Год журнала: 2024, Номер unknown, С. 123210 - 123210

Опубликована: Окт. 1, 2024

Язык: Английский

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