Combination DNA Damage Response (DDR) Inhibitors to Overcome Drug Resistance in Ovarian Cancer

Nasioudis, Dimitrios; George, Erin M.; Xu, Haineng; Kim, Hyoung; Simpkins, Fiona

doi:10.1007/978-3-031-30065-3_11

Cited by 2 publications

(1 citation statement)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study also suggested that persistent DDR signaling was activated with the formation of PGCCs and senescence in SKOV3 and A2780 cells. Aberrant activation of DDR signaling is strongly correlated with resistance of cancer cells to genotoxic anti-tumor therapeutics [ 32 , 33 ]. Many reports associate increased DDR signaling with cancer cell survival after chemotherapy, making this pathway an attractive target for overcoming cancer chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Polyploid giant cancer cells induced by Docetaxel exhibit a senescence phenotype with the expression of stem cell markers in ovarian cancer cells

Zhao,

Wang,

Ouyang

et al. 2024

PLoS ONE

View full text Add to dashboard Cite

Docetaxel (Doc) plays a crucial role in clinical antineoplastic practice. However, it is continuously documented that tumors frequently develop chemoresistance and relapse, which may be related to polyploid giant cancer cells (PGCCs). The aim of this study was investigate the formation mechanism and biological behavior of PGCCs induced by Doc. Ovarian cancer cells were treated with Doc, and then the effect of Doc on cellular viability was evaluated by MTT assay and microscopic imaging analysis. The biological properties of PGCCs were further evaluated by Hoechst 33342 staining, cell cycle and DNA content assay, DNA damage response (DDR) signaling detection, β-galactosidase staining, mitochondrial membrane potential detection, and reverse transcription-quantitative polymerase chain reaction. The results indicated that Doc reduced cellular viability; however, many cells were still alive, and were giant and polyploid. Doc increased the proportion of cells stayed in the G2/M phase and reduced the number of cells. In addition, the expression of γ-H2A.X was constantly increased after Doc treatment. PGCCs showed senescence-associated β-galactosidase activity and an increase in the monomeric form of JC-1. The mRNA level of octamer-binding transcription factor 4 (OCT4) and krüppel-like factor 4 (KLF4) was significantly increased in PGCCs. Taken together, our results suggest that Doc induces G2/M cell cycle arrest, inhibits the proliferation and activates persistent DDR signaling to promote the formation of PGCCs. Importantly, PGCCs exhibit a senescence phenotype and express stem cell markers.

show abstract

Section: Discussionmentioning

confidence: 99%

Polyploid giant cancer cells induced by Docetaxel exhibit a senescence phenotype with the expression of stem cell markers in ovarian cancer cells

Zhao,

Wang,

Ouyang

et al. 2024

PLoS ONE

View full text Add to dashboard Cite

show abstract

Insights into the Dissociation Process and Binding Pattern of the BRCT7/8-PHF8 Complex

Yuan,

Liang,

2024

ACS Omega

View full text Add to dashboard Cite

DNA topoisomerase 2-binding protein 1 (Topbp1) plays a crucial role in activating the ataxia-telangiectasia mutated and rad3-related (ATR) complex to initiate DNA damage repair responses. For this process to occur, it is necessary for PHF8 to dissociate from Topbp1. Topbp1 binds to the acidic patch sequence (APS) of PHF8 through its C-terminal BRCT7/8 domain, and disrupting this interaction could be a promising strategy for cancer treatment. To investigate the dissociation process and binding pattern of BRCT7/8-PHF8, we employed enhanced sampling techniques, such as steered molecular dynamics (SMD) simulations and accelerated molecular dynamics (aMD) simulations, along with self-organizing maps (SOM) and time-resolved force distribution analysis (TRFDA) methodologies. Our results demonstrate that the dissociation of PHF8 from BRCT7/8 starts from the N-terminus, leading to the unfolding of the N-terminal helix. Additionally, we identified critical residues that play a pivotal role in this dissociation process. These findings provide valuable insights into the disassociation of PHF8 from BRCT7/8, which could potentially guide the development of novel drugs targeting Topbp1 for cancer therapy.

show abstract

Combination DNA Damage Response (DDR) Inhibitors to Overcome Drug Resistance in Ovarian Cancer

Cited by 2 publications

References 78 publications

Polyploid giant cancer cells induced by Docetaxel exhibit a senescence phenotype with the expression of stem cell markers in ovarian cancer cells

Polyploid giant cancer cells induced by Docetaxel exhibit a senescence phenotype with the expression of stem cell markers in ovarian cancer cells

Insights into the Dissociation Process and Binding Pattern of the BRCT7/8-PHF8 Complex

Contact Info

Product

Resources

About