scholarly journals Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

Diagnostics ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 121 ◽  
Author(s):  
Brian T. Burgess ◽  
Abigail M. Anderson ◽  
J. Robert McCorkle ◽  
Jianrong Wu ◽  
Frederick R. Ueland ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Drug Sensitivity ◽  
Parp Inhibitors ◽  
Clinical Development ◽  
Cell Models ◽  
Ovarian Cells ◽  
A Cell ◽  
Increased Sensitivity ◽  
Chk1 Inhibitor

Objective: Despite the promise of PARP inhibitors (PARPi) for treating BRCA1/2 mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance. Methods: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) gBRCA1 mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score ≥ 0) or antagonistic (Bliss score ≥ 0) response of the PARPi in combination with the inhibitors. Results: IC50 for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (p = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (p = 0.04) compared to UWB1. Olaparib (0.3–1.25 µM) and ATRi (0.8–2.5 µM) were synergistic with Bliss scores of 17.2 ± 0.2, 11.9 ± 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3–1.25 µM) and Chk1i(0.05–1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively. Conclusions: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.

scholarly journals A Cell Cycle-Dependent Regulatory Circuit Composed of 53BP1-RIF1 and BRCA1-CtIP Controls DNA Repair Pathway Choice

2013 ◽  
Vol 49 (5) ◽  
pp. 872-883 ◽  
Author(s):  
Cristina Escribano-Díaz ◽  
Alexandre Orthwein ◽  
Amélie Fradet-Turcotte ◽  
Mengtan Xing ◽  
Jordan T.F. Young ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Repair Pathway ◽  
Regulatory Circuit ◽  
A Cell ◽  
Pathway Choice ◽  
Cycle Dependent

scholarly journals Doxorubicin and vincristine affect undifferentiated rat spermatogonia

Reproduction ◽  
2017 ◽  
Vol 153 (6) ◽  
pp. 725-735 ◽  
Author(s):  
Hermance Beaud ◽  
Ans van Pelt ◽  
Geraldine Delbes
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Excision Repair ◽  
Alkylating Agents ◽  
Dna Breaks ◽  
Cycle Arrest ◽  
A Cell ◽  
The Impact

Anticancer drugs, such as alkylating agents, can affect male fertility by targeting the DNA of proliferative spermatogonial stem cells (SSC). Therefore, to reduce such side effects, other chemotherapeutics are used. However, less is known about their potential genotoxicity on SSC. Moreover, DNA repair mechanisms in SSC are poorly understood. To model treatments deprived of alkylating agents that are commonly used in cancer treatment, we tested the impact of exposure to doxorubicin and vincristine, alone or in combination (MIX), on a rat spermatogonial cell line with SSC characteristics (GC-6spg). Vincristine alone induced a cell cycle arrest and cell death without genotoxic impact. On the other hand, doxorubicin and the MIX induced a dose-dependent cell death. More importantly, doxorubicin and the MIX induced DNA breaks, measured by the COMET assay, at a non-cytotoxic dose. To elucidate which DNA repair pathway is activated in spermatogonia after exposure to doxorubicin, we screened the expression of 75 genes implicated in DNA repair. Interestingly, all were expressed constitutively in GC-6spg, suggesting great potential to respond to genotoxic stress. Doxorubicin treatments affected the expression of 16 genes (>1.5 fold change;P < 0.05) involved in cell cycle, base/nucleotide excision repair, homologous recombination and non-homologous end joining (NHEJ). The significant increase in CDKN1A and XRCC1 suggest a cell cycle arrest and implies an alternative NHEJ pathway in response to doxorubicin-induced DNA breaks. Together, our results support the idea that undifferentiated spermatogonia have the ability to respond to DNA injury from chemotherapeutic compounds and escape DNA break accumulation.

scholarly journals Dynamic Alterations of Histone H3 Phospho-acetylation Correlate With Radio Sensitivity of Mitotic Cells During DNA Damage

2020 ◽  
Author(s):  
Asmita Sharda ◽  
Tripti Verma ◽  
Nikhil Gadewal ◽  
Sanjay Gupta
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Cycle Progression ◽  
Protein Translation ◽  
Chemotherapeutic Agents ◽  
Open Chromatin ◽  
Dependent Manner ◽  
A Cell ◽  
Cycle Dependent

Abstract Background - Histone Post Translational Modifications (PTMs) change in a cell cycle dependent manner and also orchestrate the DNA repair process for radiation induced DNA damage. Mitosis is the most radiosensitive phase of the cell cycle but the epigenetic events that regulate its radiosensitivity remain elusive.Results - This study explored the dynamics between histone marks H3S10/S28ph, H3K9ac and γH2AX during mitotic DNA damage response. The presence of a mononucleosome level association between γH2AX and H3S10ph was observed only during mitosis. This association was abrogated upon cell cycle progression and chromatin de-condensation, concomitant with chromatin recruitment of DNA repair proteins Ku70 and Rad51. Moreover, the levels of H3S10/28ph remained unchanged upon DNA damage during mitosis, but decreased in a cell cycle dependent manner upon mitotic exit. However, the population that arose after mitotic progression of damaged cells comprised of binucleated tetraploid cells. This population was epigenetically distinct from interphase cells, characterized by reduced H3S10/S28ph, increased H3K9ac and more open chromatin configuration. These epigenetic features correlated with decreased survival potential of this population. The low levels of H3S10/28ph were attributed to decreased protein translation and chromatin recruitment of histone kinase Mitogen and Stress-activated Kinase 1 (MSK1) along with persistent levels of Protein phosphatase1 catalytic subunit α (PP1α). Conclusions – This study suggests that a unique epigenetic landscape attained during and after mitotic DNA damage collectively contributed to mitotic radiosensitivity. The findings of this study have potential clinical significance in terms of tackling resistance against anti-mitotic chemotherapeutic agents.

Imaging with FLT-PET demonstrates that PF-477736, an inhibitor of CHK1 kinase, overcomes a cell cycle checkpoint induced by gemcitabine in PC-3 xenografts

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3045-3045 ◽  
Author(s):  
G. A. McArthur ◽  
J. Raleigh ◽  
A. Blasina ◽  
C. Cullinane ◽  
D. Dorow ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Fold Increase ◽  
Cell Cycle Checkpoint ◽  
Flt Pet ◽  
Cycle Arrest ◽  
Cycle Checkpoint ◽  
A Cell ◽  
Chk1 Inhibitor

3045 Background: The development of strategies to monitor the molecular and cellular response to novel agents that target the cell cycle is vital to provide proof of mechanism and biological activity of these compounds. The protein kinase CHK1 is activated following DNA damage in the S and G2-phases of the cell cycle and mediates cell cycle arrest. In vitro studies demonstrate that inhibition of CHK1 can overcome cell cycle arrest induced by DNA damage and enhance cytotoxic activity of DNA damaging agents. In vivo studies show that combining DNA damaging agents with a CHK1 inhibitor potentiates antitumor activity. We hypothesize that functional imaging with 18F-fluorine-L-thymidine (FLT), a PET-tracer where tumor uptake is maximal in the S and G2 phases of the cell cycle can be used to non-invasively monitor the induction and therapeutic inhibition of a cell cycle checkpoint in vivo. Methods: Nude mice harbouring PC-3 xenografts were treated with vehicle controls, gemcitabine, the CHK1-inhibitor PF-477736 or gemcitabine + PF-477736. FLT-PET scans were performed and tumors harvested for ex-vivo biomarkers to assess S-phase, M-phase and DNA-repair. Results: Gemcitabine induced a 8.3 ±0.8 fold increase in tumoral uptake of FLT at 21 hours that correlated with a 3.3 ±0.2-fold increase in thymidine kinase activity and S-phase arrest as demonstrated by BrdU incorporation and elevated expression of cyclin-A. Treatment with PF-477736 at 17 hours after gemcitabine abrogated the early FLT-flare at 21 hours by 82% (p<0.001). This was associated with both an increased fraction of cells in mitosis and G1-phase of the cell cycle as determined by phos-histone H3 and flow cytometry. Furthermore, the combination of gemcitabine and PF-477736 enhanced DNA damage as measured by phos-gamma-H2AX and significantly delayed tumor growth when compared to tumors treated with gemcitabine alone. Conclusion: These data clearly indicate that the CHK1-inhibitor PF-477736 can overcome the cell cycle checkpoint induced by gemcitabine and increase associated DNA damage in tumors in-vivo. The PET studies indicate that functional imaging with FLT-PET is a promising strategy to monitor responses to therapeutic agents that target cell cycle checkpoints. [Table: see text]

scholarly journals A cell cycle-regulated Slx4-Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication

2014 ◽  
Vol 28 (14) ◽  
pp. 1604-1619 ◽  
Author(s):  
D. Gritenaite ◽  
L. N. Princz ◽  
B. Szakal ◽  
S. C. S. Bantele ◽  
L. Wendeler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
A Cell

scholarly journals The Less Known Cyclins—Uncovered

2021 ◽  
Vol 11 (5) ◽  
pp. 2320
Author(s):  
Agnieszka Żuryń ◽  
Aleksandra Opacka ◽  
Adrian Krajewski ◽  
Wioletta Zielińska ◽  
Alina Grzanka
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Cell Differentiation ◽  
Cancer Cells ◽  
Present Report ◽  
Life Stage ◽  
Cyclin Dependent Kinases ◽  
Current State ◽  
Different Types ◽  
A Cell

Cyclins belong to a group of proteins that are cyclically produced and destructed in a cell. Cyclins are a family of proteins that are a key component of the cell cycle regulating system, which level of expression depends on the phase of the cycle. Cyclins regulate the activity of cyclin-dependent kinases (Cdk), thanks to which they influence the length of individual phases of the cell cycle and also determine whether the cell can enter the next life stage. Proper expression of cyclins plays an important role in processes such as proliferation, transcription, DNA repair and cell differentiation. However, dysregulation of their expression is one of the most important disorders leading to the development of different types of cancer, which suggests that cyclins can be defined as a prognostic marker. Currently, we may distinguish >10 members of the cyclins family participating in the division of human cells. The group of less known cyclins includes C, F, G, H, I, J, K, L, M, O, T and Y cyclins. The present report demonstrates the current state of knowledge considering less known cyclins and their role in normal and cancer cells.

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