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TargetMol—Star Molecule—Etoposide (Cat. No. T0132, CAS 33419-42-0), a Classic Topoisomerase II Inhibitor for Dissecting DNA Damage Responses
Background
Etoposide (T0132) is a potent inhibitor of topoisomerase II, an essential enzyme that modulates DNA topology during replication and transcription by inducing transient double-strand breaks. By stabilizing the topoisomerase II-DNA cleavage complex, Etoposide effectively prevents the relegation of DNA strands, thereby halting DNA synthesis and triggering DNA damage responses. This mechanism underpins its ability to induce apoptosis, a programmed cell death pathway, as well as autophagy and mitophagy, which are cellular degradation processes involved in maintaining homeostasis and responding to stress. The topoisomerase II inhibition by Etoposide leads to accumulation of DNA breaks, activating signaling cascades that engage apoptotic effectors such as caspases and autophagic machinery components like LC3 and Beclin-1. Additionally, Etoposide’s interference with mitochondrial integrity can promote mitophagy, selectively removing damaged mitochondria to regulate cellular metabolism and survival pathways. Beyond its role in apoptosis and autophagy, Etoposide exhibits antibacterial and antibiotic properties, likely through its interaction with bacterial topoisomerases, which share mechanistic similarities with eukaryotic topoisomerase II. In research contexts, Etoposide is widely utilized as a molecular tool to dissect DNA damage responses, apoptosis signaling, and autophagic flux, providing insights into cellular stress pathways and mitochondrial quality control. Its capacity to induce DNA damage and modulate multiple cell death and survival pathways makes it invaluable for studying the interplay between genomic integrity and cellular homeostasis. Furthermore, Etoposide’s effects on bacterial topoisomerases offer a model for exploring antibiotic mechanisms and resistance. Overall, Etoposide serves as a critical compound for investigating topoisomerase II function, apoptosis, autophagy, and mitophagy, facilitating advances in understanding cellular responses to DNA damage and mitochondrial dysfunction [1,2].
Molecular Formula of Etoposide
Literature review
2.1 Anti-apoptotic Mutations Desensitize Human Pluripotent Stem Cells to Mitotic Stress and Enable Aneuploid Cell Survival
Etoposide(T0132) induced apoptosis in human pluripotent stem cells through a mechanism involving TP53. Treatment with etoposide led to a massive increase in TP53 protein levels in control cells, indicating activation of the TP53 pathway. When TP53 was knocked down by shRNA in H9 cells, apoptosis caused by etoposide was dramatically alleviated, demonstrating that TP53 is critical for DNA damage-induced apoptosis by etoposide. In contrast, TP53 did not mediate apoptosis induced by mitotic arrest, as knockdown of TP53 did not reduce cell death following nocodazole treatment. These results clarify that etoposide prompts a TP53-dependent apoptotic response in hPSCs linked to DNA damage, confirming its effect on cell death via the DNA damage pathway.[3]
2.2 Non canonical BRCA1 promotes cell survival via modulating PARP13-mediated SEC61G mRNA decay
Etoposide(T0132) significantly enhanced the stability of SEC61G mRNA in wild-type A2780 cells, which was associated with an increase in SEC61G protein expression. The drug treatment also increased intracellular calcium concentration, a process linked to the BRCA1/PARP13-SEC61G axis. Flow cytometry analysis demonstrated that cells deficient in BRCA1 or PARP13 exhibited reduced cytosolic calcium levels upon etoposide exposure compared to wild-type cells, indicating that etoposide facilitates calcium flux into the cytosol. Concurrently, etoposide remarkably activated the pro-survival kinase Akt in wild-type cells in a dose-dependent manner; however, this activation was absent in BRCA1 or PARP13 knockout cells. Knockdown of SEC61G abolished this Akt activation, underscoring the dependency of this signaling on SEC61G. Additionally, calcium chelation with BAPTA-AM eliminated Akt phosphorylation induced by etoposide, confirming the role of calcium flux in the activation of Akt. Cell viability was reduced in PARP13 knockout cells following etoposide treatment, further supporting the role of the BRCA1/PARP13-SEC61G axis in enhancing cellular survival signals through calcium-mediated Akt activation in response to DNA damage mediated by etoposide.[4]
Reference
[1] Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009 May;9(5):338-50.
[2] Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999 Sep 1;57(7):727-41.
[3] Zhang J, Hirst A, Duan F, Qiu H, Huang R, Ji Y, et al.. Anti-apoptotic Mutations Desensitize Human Pluripotent Stem Cells to Mitotic Stress and Enable Aneuploid Cell Survival. Stem Cell Reports. 2019;12(3):557-571.
[4] Sun B, Li Y, Wu Y, Wang C, Zhu J, Zhang W, et al.. Non canonical BRCA1 promotes cell survival via modulating PARP13-mediated SEC61G mRNA decay. Oncogenesis. 2025;14(1):.
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