Stimulation of Topoisomerase II-Mediated DNA Damage via a Mechanism Involving Protein Thiolation†

Biochemistry ◽  
2001 ◽  
Vol 40 (11) ◽  
pp. 3316-3323 ◽  
Author(s):  
Huimin Wang ◽  
Yong Mao ◽  
Allan Y. Chen ◽  
Nai Zhou ◽  
Edmond J. LaVoie ◽  
...  
Keyword(s):  
Dna Damage ◽  
Topoisomerase Ii ◽  
Stimulation Of

Evidence for a Role of Vertebrate Rad52 in the Repair of Topoisomerase II–Mediated DNA Damage

2005 ◽  
Vol 24 (6) ◽  
pp. 388-393 ◽  
Author(s):  
Noritaka Adachi ◽  
Susumu Iiizumi ◽  
Hideki Koyama
Keyword(s):  
Dna Damage ◽  
Topoisomerase Ii

scholarly journals Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both Topoisomerase II isoforms

BMC Cancer ◽  
2014 ◽  
Vol 14 (1) ◽  
Author(s):  
Shiwei Deng ◽  
Tiandong Yan ◽  
Cathleen Jendrny ◽  
Andrea Nemecek ◽  
Mladen Vincetic ◽  
...  
Keyword(s):  
Dna Damage ◽  
Topoisomerase Ii

scholarly journals Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair

2020 ◽  
Vol 21 (22) ◽  
pp. 8842
Author(s):  
Sergei Boichuk ◽  
Firuza Bikinieva ◽  
Ilmira Nurgatina ◽  
Pavel Dunaev ◽  
Elena Valeeva ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Soft Tissue ◽  
Gastrointestinal Stromal Tumors ◽  
Topoisomerase Ii ◽  
Soft Tissue Sarcomas ◽  
Akt Signaling ◽  
Chemotherapeutic Agents ◽  
Tail Moment ◽  
Stromal Tumors

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is well documented for a broad spectrum of human malignancies supporting their growth and progression. Accumulating evidence has also implicated AKT as a potent modulator of anti-cancer therapies via regulation of DNA damage response and repair (DDR) induced by certain chemotherapeutic agents and ionizing radiation (IR). In the present study, we examined the role of AKT signaling in regulating of Rad51 turnover and cytotoxic effects of topoisomerase II inhibitor, doxorubicin (Dox) in soft tissue sarcomas (STS) and gastrointestinal stromal tumors (GIST) in vitro. Blocking of AKT signaling (MK-2206) enhanced cytotoxic and pro-apoptotic effects of Dox in vast majority of STS and GIST cell lines. The phosphorylated form of Akt co-immunoprecipitates with Rad51 after Dox-induced DNA damage, whereas Akt inhibition interrupts this interaction and decreases Rad51 protein level by enhancing protein instability via proteasome-dependent degradation. Inhibition of Akt signaling in Dox-treated cells was associated with the increased number of γ-H2AX-positive cells, decrease of Rad51 foci formation and its colocalization with γ-H2AX foci, thereby revealing unsuccessful DDR events. This was also in consistency with an increase of tail moment (TM) and olive tail moment (OTM) in Dox-treated GIST and STS cells cultured in presence of Akt inhibitor after Dox washout. Altogether, our data illustrates that inhibition of AKT signaling is STS and GIST might potentiate the cytotoxic effect of topoisomerase II inhibitors via attenuating the homology-mediated DNA repair.

Roles of nonhomologous end-joining pathways in surviving topoisomerase II–mediated DNA damage

2006 ◽  
Vol 5 (6) ◽  
pp. 1405-1414 ◽  
Author(s):  
Mobeen Malik ◽  
Karin C. Nitiss ◽  
Vanessa Enriquez-Rios ◽  
John L. Nitiss
Keyword(s):  
Dna Damage ◽  
Topoisomerase Ii ◽  
Nonhomologous End Joining ◽  
End Joining

Abstract 842: DNA opilymerase β participates in the repair of DNA damage from topoisomerase II

2014 ◽  
Author(s):  
Yilun Sun ◽  
Sule Bertram ◽  
John L. Nitiss
Keyword(s):  
Dna Damage ◽  
Topoisomerase Ii

scholarly journals The ascidian natural product eusynstyelamide B is a novel topoisomerase II poison that induces DNA damage and growth arrest in prostate and breast cancer cells

Oncotarget ◽  
2015 ◽  
Vol 6 (41) ◽  
pp. 43944-43963 ◽  
Author(s):  
Michelle S. Liberio ◽  
Martin C. Sadowski ◽  
Rohan A. Davis ◽  
Anja Rockstroh ◽  
Raj Vasireddy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Natural Product ◽  
Breast Cancer Cells ◽  
Topoisomerase Ii ◽  
Growth Arrest

Honokiol Induces Autophagic Apoptosis in Neuroblastoma Cells through a P53-Dependent Pathway

2019 ◽  
Vol 47 (04) ◽  
pp. 895-912 ◽  
Author(s):  
Ming-Chung Lin ◽  
Yuan-Wen Lee ◽  
Yuan-Yun Tseng ◽  
Yung-Wei Lin ◽  
Jui-Tai Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Therapeutic Option ◽  
Neuroblastoma Cells ◽  
Cytochrome C Release ◽  
Dependent Pathway ◽  
Dependent Mechanism ◽  
Stimulation Of

In children, neuroblastomas are the most common and deadly solid tumor. Our previous studies showed that honokiol can cross the blood–brain barrier and kill neuroblastoma cells. In this study, we further evaluated if exposure to honokiol for short periods could induce autophagy and subsequent apoptosis of neuroblastoma cells and possible mechanisms. Exposure of neuroblastoma neuro-2a cells to honokiol for 24[Formula: see text]h induced morphological shrinkage and cell death. As to the mechanisms, honokiol consecutively induced cytochrome c release from mitochondria, caspase-3 activation, DNA fragmentation and cell apoptosis. Separately, honokiol time-dependently augmented the proportion of autophagic cells and the ratio of light chain 3 (LC3)-II/LC3-I. Pretreatment of neuro-2a cells with 3-methyladenine, an inhibitor of autophagy, attenuated honokiol-induced cell autophagy, caspase-3 activation, DNA damage and cell apoptosis. In contrast, stimulation of autophagy by rapamycin, an inducer of autophagy, significantly enhanced honokiol-induced cell apoptosis. Furthermore, honokiol-induced autophagic apoptosis was confirmed in neuroblastoma NB41A3 cells. Knocking down translation of p53 using RNA interference attenuated honokiol-induced autophagy and apoptosis in neuro-2a and NB41A3 cells. Taken together, this study showed that at early periods, honokiol can induce autophagic apoptosis of neuroblastoma cells through activating a p53-dependent mechanism. Consequently, honokiol has the potential to be a therapeutic option for neuroblastomas.

scholarly journals DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

2004 ◽  
Vol 3 (1) ◽  
pp. 82-90 ◽  
Author(s):  
Mobeen Malik ◽  
John L. Nitiss
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Excision Repair ◽  
Dna Strand Breaks ◽  
Dna Topology ◽  
Strand Breaks ◽  
Wide Range ◽  
Dna Strand

ABSTRACT DNA topoisomerases play critical roles in a wide range of cellular processes by altering DNA topology to facilitate replication, transcription, and chromosome segregation. Topoisomerases alter DNA topology by introducing transient DNA strand breaks that involve a covalent protein DNA intermediate. Many agents have been found to prevent the religation of DNA strand breaks induced by the enzymes, thereby converting the enzymes into DNA-damaging agents. Repair of the DNA damage induced by topoisomerases is significant in understanding drug resistance arising following treatment with topoisomerase-targeting drugs. We have used the fission yeast Schizosaccharomyces pombe to identify DNA repair pathways that are important for cell survival following drug treatment. S. pombe strains carrying mutations in genes required for homologous recombination such as rad22A or rad32 (homologues of RAD52 and MRE11) are hypersensitive to drugs targeting either topoisomerase I or topoisomerase II. In contrast to results observed with Saccharomyces cerevisiae, S. pombe strains defective in nucleotide excision repair are also hypersensitive to topoisomerase-targeting agents. The loss of DNA replication or DNA damage checkpoints also sensitizes cells to both topoisomerase I and topoisomerase II inhibitors. Finally, repair genes (such as the S. pombe rad8+ gene) with no obvious homologs in other systems also play important roles in causing sensitivity to topoisomerase drugs. Since the pattern of sensitivity is distinct from that seen with other systems (such as the S. cerevisiae system), our results highlight the usefulness of S. pombe in understanding how cells deal with the unique DNA damage induced by topoisomerases.

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