Ouabain Induces DNA Damage in Human Osteosarcoma U-2 OS Cells and Alters the Expression of DNA Damage and DNA Repair–associated Proteins

Yang, Jun; Yang, Mei‐Due; Chen, Jaw-Chyun; Lu, Kung‐Wen; Huang, Yiping; Peng, Shu‐Fen; Chueh, Fu‐Shin; Liu, Kuo-Ching; Lin, Tzu-Shun; Chen, Po‐Yuan; Chen, Wei-Jen

doi:10.21873/invivo.12552

Cited by 4 publications

(6 citation statements)

References 51 publications

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“…A recent study demonstrated that ouabain can promote cytotoxicity in U2OS osteosarcoma cells via apoptotic cell death [ 55 ]. Another study validated this observation and implicated the DDR pathway [ 30 ]. Experiments performed using the comet assay and DNA electrophoresis revealed that ouabain induces DNA breaks and DNA fragmentation [ 30 ].…”

Section: Mechanism Of Cgs Via Dna Damage Signalingmentioning

confidence: 61%

“…Another study validated this observation and implicated the DDR pathway [ 30 ]. Experiments performed using the comet assay and DNA electrophoresis revealed that ouabain induces DNA breaks and DNA fragmentation [ 30 ]. The authors also reported increased phosphorylation and expression of several DNA damage proteins such as ATM, ATR, p53, γ-H2A histone family member X (γ-H2AX), mediator of DNA damage checkpoint 1 (MDC-1), PARP, and breast cancer gene 1 (BRCA1) (Fig.…”

Section: Mechanism Of Cgs Via Dna Damage Signalingmentioning

confidence: 61%

“…2 ) show minimal hydroxylation on the steroid frame. But, if the vast interests and current applications of ouabain in research are any indication [ 24 , 30 , 53 – 55 ], hydroxylation of the steroid core might be an avenue worth exploring. However, one of the challenges with these bioactive compounds is the limited opportunity for functionalization, especially on the steroid core.…”

Section: Structural Function and Physicochemical Properties Of Cgsmentioning

confidence: 99%

“…This is an important stride in overcoming drug resistance and increasing the efficacy of these therapeutics. CGs have also been shown to cause various types of DNA damage such as DSBs, SSBs, and ICLs, whereas some forms of damage are exacerbated by the formation of ROS [ 13 , 30 , 31 , 53 ]. Once induced, DNA damage activates signaling kinases that trigger responses including transcription, cell cycle arrest, and apoptosis.…”

Section: Perspective and Conclusionmentioning

confidence: 99%

“…Finally, effects on transcription, splicing, and translation have also been reported [ 29 ]. Multiple studies implicate the DNA damage response (DDR), and reduced expression of DNA repair proteins and kinases has been reported with GC treatment [ 30 , 31 ], and interactions with the ubiquitin-like with PHD and RING finger domains protein 1 (UHRF1) [ 32 ]. More recently, Zhou et al reported that a synthetic CG induces parthanatos via overexpression of poly-ADP ribose polymerase (PARP) and poly-ADP ribose (PAR) which are triggered by DNA damaging agents [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

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The mechanistic role of cardiac glycosides in DNA damage response and repair signaling

Ainembabazi

Zhang

Turchi

2023

Cell. Mol. Life Sci.

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Cardiac glycosides (CGs) are a class of bioactive organic compounds well-known for their application in treating heart disease despite a narrow therapeutic window. Considerable evidence has demonstrated the potential to repurpose CGs for cancer treatment. Chemical modification of these CGs has been utilized in attempts to increase their anti-cancer properties; however, this has met limited success as their mechanism of action is still speculative. Recent studies have identified the DNA damage response (DDR) pathway as a target of CGs. DDR serves to coordinate numerous cellular pathways to initiate cell cycle arrest, promote DNA repair, regulate replication fork firing and protection, or induce apoptosis to avoid the survival of cells with DNA damage or cells carrying mutations. Understanding the modus operandi of cardiac glycosides will provide critical information to better address improvements in potency, reduced toxicity, and the potential to overcome drug resistance. This review summarizes recent scientific findings of the molecular mechanisms of cardiac glycosides affecting the DDR signaling pathway in cancer therapeutics from 2010 to 2022. We focus on the structural and functional differences of CGs toward identifying the critical features for DDR targeting of these agents.

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Section: Mechanism Of Cgs Via Dna Damage Signalingmentioning

confidence: 61%

Section: Mechanism Of Cgs Via Dna Damage Signalingmentioning

confidence: 61%

Section: Structural Function and Physicochemical Properties Of Cgsmentioning

confidence: 99%

Section: Perspective and Conclusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mechanistic role of cardiac glycosides in DNA damage response and repair signaling

Ainembabazi

Zhang

Turchi

2023

Cell. Mol. Life Sci.

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PEITC Induces DNA Damage and Inhibits DNA Repair‐Associated Proteins in Human Retinoblastoma Cells In Vitro

Hsu,

Huang,

Hsia

et al. 2024

Environmental Toxicology

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Phenethyl isothiocyanate (PEITC), a natural product, exists in biological activities, including anticancer activity in many human cancer cells. No information shows that PEITC affects DNA damage in human retinoblastoma (RB) cells in vitro. In this study, the aim of experiments was to determine whether PEITC decreased total viable cell number or not by inducing protein expressions involved in DNA damage and repair in Y79 RB cells in vitro. Total cell viability was measured by PI exclusion assay, and PEITC reduced the total Y79 viable cell numbers in a dose‐dependent manner. DNA condensation and DNA impairment were conducted by DAPI staining and comet assays, respectively, in Y79 cells. The findings show that PEITC induced DNA condensation dose‐dependently based on the brighter fluorescence of cell nuclei stained by DAPI staining. PEITC‐induced DNA damage showed a more extended DNA migration smears than that of the control, which was performed by a comet assay. Western blotting was performed to measure the protein expressions involved in DNA damage and repair, which showed that PEITC at 2.5–10 μM increased NRF2, HO‐1, SOD (Mn), and catalase; however, it decreased SOD (Cu/Zn) except 10 μM PEITC treatment, and decreased glutathione, which were associated with oxidative stress. Furthermore, PEITC increased DNA‐PK, MDC1, H2A.XpSer139, ATMpSer1981, p53, p53pSer15, PARP, HSP70, and HSP90, but decreased TOPIIα, TOPIIβ, and MDM2pSer166 that were associated with DNA damage and repair mechanism in Y79 cells. The examination from confocal laser microscopy shows that PEITC increased H2A.XpSer139 and p53pSer15, and decreased glutathione and TOPIIα in Y79 cells. In conclusion, the cytotoxic effects of PEITC on reducing the number of viable cells may be due to the induction of DNA damage and the alteration of DNA repair proteins in Y79 cells in vitro.

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Digoxin and its Na+/K+-ATPase-targeted actions on cardiovascular diseases and cancer

Ren,

Anderson,

Meyer

et al. 2024

Bioorganic & Medicinal Chemistry

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Ouabain Induces DNA Damage in Human Osteosarcoma U-2 OS Cells and Alters the Expression of DNA Damage and DNA Repair–associated Proteins

Cited by 4 publications

References 51 publications

The mechanistic role of cardiac glycosides in DNA damage response and repair signaling

The mechanistic role of cardiac glycosides in DNA damage response and repair signaling

PEITC Induces DNA Damage and Inhibits DNA Repair‐Associated Proteins in Human Retinoblastoma Cells In Vitro

Digoxin and its Na+/K+-ATPase-targeted actions on cardiovascular diseases and cancer

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