Topoisomerase II and tubulin inhibitors both induce the formation of apoptotic topoisomerase I cleavage complexes

Sordet, Olivier; Goldman, Abby R.; Pommier, ﻿Yves

doi:10.1158/1535-7163.mct-06-0463

Cited by 30 publications

(31 citation statements)

References 32 publications

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“…Results indicate that, along with topoisomerase I-DNA cleavable complexes, topoisomerase II covalent complexes are also formed after etoposide treatment. These topoisomerase II-DNA covalent complexes leads to ROS generation, which subsequently leads to apoptotic topoisomerase I-DNA cleavable complexes (11). Pretreatment with betulinic acid can reduce topoisomerase II-DNA covalent complexes as evidenced in immunoband depletion assay (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Although the effect of betulinic acid on topoisomerase I-DNA complexes are partly due to the inhibition of topoisomerase II-DNA complexes, it, however, does not affect our conclusion significantly. It has been shown that it is the topoisomerase I cleavable complexes and not the topoisomerase II complexes which are responsible for mediating apoptotic cell death by etoposide (11). To check whether staurosporine also have any effect on topoisomerase II-DNA cleavable complexes, we performed immunoband depletion assays after staurosporine treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Pommier and coworkers have established that topoisomerase I-DNA cleavable complexes are formed in cells exposed to staurosporine (9), arsenic trioxide (10), etoposide (11), and vinblastin (11), which are mechanistically different inducers of apoptosis. All these compounds are inactive on purified topoisomerase I in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Betulinic Acid, a Catalytic Inhibitor of Topoisomerase I, Inhibits Reactive Oxygen Species–Mediated Apoptotic Topoisomerase I–DNA Cleavable Complex Formation in Prostate Cancer Cells but Does Not Affect the Process of Cell Death

Ganguly¹,

Das

Roy³

et al. 2007

Cancer Research

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The ubiquitious enzyme topoisomerase I can be targeted by drugs which turn these enzymes into cellular poisons and subsequently induce cell death. Drugs like staurosporine, which do not target topoisomerase I directly, can also lead to stabilization of topoisomerase I-DNA cleavable complexes by an indirect process of reactive oxygen species (ROS) generation and subsequent oxidative DNA damage. In this study, we show that betulinic acid, a catalytic inhibitor of topoisomerases, inhibits the formation of apoptotic topoisomerase I-DNA cleavable complexes in prostate cancer cells induced by drugs like camptothecin, staurosporine, and etoposide. Although events like ROS generation, oxidative DNA damage, and DNA fragmentation were observed after betulinic acid treatment, there is no topoisomerase I-DNA cleavable complex formation, which is a key step in ROS-induced apoptotic processes. We have shown that betulinic acid interacts with cellular topoisomerase I and prohibits its interaction with the oxidatively damaged DNA. Using oligonucleotide containing 8-oxoguanosine modification, we have shown that betulinic acid inhibits its cleavage by topoisomerase I in vitro. Whereas silencing of topoisomerase I gene by small interfering RNA reduces cell death in the case of staurosporine and camptothecin, it cannot substantially reduce betulinic acidinduced cell death. Thus, our study provides evidence that betulinic acid inhibits formation of apoptotic topoisomerase I-DNA complexes and prevents the cellular topoisomerase I from directly participating in the apoptotic process. [Cancer Res 2007;67(24):11848-58]

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

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Betulinic Acid, a Catalytic Inhibitor of Topoisomerase I, Inhibits Reactive Oxygen Species–Mediated Apoptotic Topoisomerase I–DNA Cleavable Complex Formation in Prostate Cancer Cells but Does Not Affect the Process of Cell Death

Ganguly¹,

Das

Roy³

et al. 2007

Cancer Research

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“…The sample was embedded in epoxy resin and cured in 55°C oven for 48 h. The cured block was thin sectioned and stained in uranyl acetate and lead citrate and examined by electron microscopy (Hitachi H700 microscope, Tokyo, Japan). Caspase activities were measured as described (18) using the fluorogenic peptide substrate Z-DEVD-AFC (caspase-3) and Z-IETD-AFC (caspase-8) from Calbiochem.…”

Section: Methodsmentioning

confidence: 99%

“…Top1cc have also been detected in cells undergoing apoptosis in response to a wide range of stimuli, including arsenic trioxide (15), staurosporine (16), tubulin and topoisomerase II (Top2) inhibitors (17,18), TNF␣ (17), and UV-C radiation (19). In the present study, we demonstrated that apoptotic Top1cc also form in response to the physiological ligands TRAIL and Fas.…”

Section: Tumor Necrosis Factor-related Apoptosis-inducing Ligand (Trail)mentioning

confidence: 99%

Topoisomerase I Requirement for Death Receptor-induced Apoptotic Nuclear Fission

Sordet

Goldman

Redon

et al. 2008

Journal of Biological Chemistry

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Topoisomerase I (Top1) is known to relax DNA supercoiling generated by transcription, replication, and chromatin remodeling. However, it can be trapped on DNA as cleavage complexes (Top1cc) by oxidative and carcinogenic DNA lesions, base damage, and camptothecin treatment. We show here that Top1 is also functionally involved in death receptor-induced programmed cell death. In cells exposed to TRAIL or Fas ligand, Top1cc form at the onset of apoptosis. Those apoptotic Top1cc are prevented by caspase inhibition and Bax inactivation, indicating that both caspases and the mitochondrial death pathway are required for their formation. Accordingly, direct activation of the mitochondrial pathway by BH3 mimetic molecules induces apoptotic Top1cc. We also show that TRAIL-induced apoptotic Top1cc are preferentially formed by caspase-3-cleaved Top1 at sites of oxidative DNA lesions with an average of one apoptotic Top1cc/100 kbp. Examination of Top1 knockdown cells treated with TRAIL revealed similar DNA fragmentation but a marked decrease in apoptotic nuclear fission with reduced formation of nuclear bodies. Thus, we propose that Top1 contributes to the full apoptotic responses induced by TRAIL.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 2 is a promising therapeutic agent because it induces apoptosis in a wide variety of cancer cells without affecting normal tissues (1, 2). TRAIL belongs to the TNF family of cytokines, including TNF␣ and Fas ligand, which induce apoptosis by binding to their cognate plasma membrane receptors (3). The binding of TRAIL to the DR4 or DR5 receptors and the binding of Fas ligand to Fas receptor cause the intracellular death domains of those receptors to trimerize, which leads to the recruitment of FADD and the activation of caspase-8. Caspase-8 then cleaves and thereby activates caspase-3 either directly (type I cells) or/and indirectly (type II cells) (4) by activating the mitochondrial death pathway through the cleavage of Bid (5). Cleaved Bid binds to and activates the pro-apoptotic Bcl-2 relatives Bax and Bak proteins, causing the release of mitochondrial cytochrome c and the activation of caspase-9 and caspase-3 (6). Activated caspase-3 (and other downstream caspases) cleaves a broad array of intracellular targets including DNA topoisomerase I (Top1) (7). It is also required to induce the controlled rearrangement and degradation of nuclear structures with chromatin condensation, DNA fragmentation, nuclear fission, and release of apoptotic nuclear bodies in the extracellular space (8). TRAIL-induced apoptosis also involves an accumulation of intracellular reactive oxygen species (ROS) (9).Top1 removes DNA superhelical tensions generated during transcription, replication, and chromatin remodeling (10) and is essential in higher eukaryotes (11). It relaxes DNA by forming transient DNA single-strand breaks that are produced as Top1 forms a covalent bond between its active site tyrosine (Tyr 723 ) and a 3Ј-DNA phosphate. These Top1 cleavage complexes (Top1cc) allow con...

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Critical roles of tyrosyl‐DNA phosphodiesterases in cell tolerance to carnosol‐induced DNA damage

Feng

et al. 2020

Cell Biology International

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Carnosol is a natural compound with pharmacological action due to its anti‐cancer properties. However, the precise mechanism for its anti‐carcinogenic effect remains elusive. In this study, we used lymphoblastoid TK6 cell lines to identify the DNA damage and repair mechanisms of carnosol. Our results showed that carnosol induced DNA double‐strand breaks (DSBs). We also found that cells lacking tyrosyl‐DNA phosphodiesterase 1 (TDP1), an enzyme related to topoisomerase 1 (TOP1), and tyrosyl‐DNA phosphodiesterase 2 (TDP2), an enzyme related to topoisomerase 2 (TOP2), were supersensitive to carnosol. Carnosol was found to induce the formation of the TOP1‐DNA cleavage complex (TOP1cc) and TOP2‐DNA cleavage complex (TOP2cc). When comparing the accumulation of γ‐H2AX foci and the number of chromosomal aberrations (CAs) with wild‐type (WT) cells, the susceptivity of the TDP1−/− and TDP2−/− cells were associated with an increased DNA damage. Our results provided evidence of carnosol inducing DNA lesions in TK6 cells and demonstrated that the damage induced by carnosol was associated with abnormal topoisomerase activity. We conclude that TDP1 and TDP2 play important roles in the anti‐cancer effect of carnosol.

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Topoisomerase II and tubulin inhibitors both induce the formation of apoptotic topoisomerase I cleavage complexes

Cited by 30 publications

References 32 publications

Betulinic Acid, a Catalytic Inhibitor of Topoisomerase I, Inhibits Reactive Oxygen Species–Mediated Apoptotic Topoisomerase I–DNA Cleavable Complex Formation in Prostate Cancer Cells but Does Not Affect the Process of Cell Death

Betulinic Acid, a Catalytic Inhibitor of Topoisomerase I, Inhibits Reactive Oxygen Species–Mediated Apoptotic Topoisomerase I–DNA Cleavable Complex Formation in Prostate Cancer Cells but Does Not Affect the Process of Cell Death

Topoisomerase I Requirement for Death Receptor-induced Apoptotic Nuclear Fission

Critical roles of tyrosyl‐DNA phosphodiesterases in cell tolerance to carnosol‐induced DNA damage

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