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Targeting ATR Kinase as a Strategy for Canine Lymphoma and Leukaemia Treatment
Marta Henklewska1, Aleksandra Pawlak1, Bożena Obmińska-Mrukowicz1
1Department of Pharmacology and Toxicology, Wrocław University of Environmental and Life Sciences, Wrocław, Poland.
Abstract:
Ataxia telangiectasia and Rad3-related (ATR) kinase is one of the main regulators of cell response to DNA damage and replication stress. Effectiveness of ATR targeting in human cancers has been confirmed in preclinical studies and ATR inhibitors are currently developed clinically in human oncology. In the presented study, we tested the anticancer efficacy of ATR inhibitor berzosertib in an in vitro model of canine haematopoietic cancers. Using MTT assay and flow cytometry, we assessed the cytotoxicity of berzosertib in four established canine lymphoma and leukaemia cell lines and compared it with its activity against noncancerous canine cells. Further, we estimated the level of apoptosis in berzosertib-treated cells via flow cytometry and assessed H2AX phosphorylation as a marker of DNA damage using western blot technique. In flow-cytometric analysis, we also evaluated potential synergism between berzosertib and chlorambucil and assessed the influence of berzosertib on cell cycle disturbances induced by the drug. The results demonstrated that berzosertib, even without additional DNA damaging agent, can be effective against canine lymphoma and leukaemia cells at concentrations that were harmless for noncancerous cells, although sensitivity of individual cancer cell lines varied greatly. Cell death occurred through caspase-dependent apoptosis via induction of DNA damage. Berzosertib also acted synergistically with chlorambucil, probably by preventing DNA damage repair as a consequence of S-phase arrest abrogation. In conclusion, ATR inhibition may provide a new therapeutic option for the treatment of canine lymphomas and leukaemias, but further studies are required to determine potential biomarkers of their susceptibility.
Insights
Ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor berzosertib shows promise in treating canine lymphoma and leukemia. This ATR inhibitor effectively targets cancer cells while sparing normal cells, indicating a potential new therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Veterinary Medicine
Background:
- Ataxia telangiectasia and Rad3-related (ATR) kinase is crucial for cellular response to DNA damage and replication stress.
- ATR inhibitors have demonstrated efficacy in preclinical cancer studies and are under clinical development for human oncology.
- Canine hematopoietic cancers, such as lymphoma and leukemia, represent a significant area for therapeutic innovation.
Purpose of the Study:
- To evaluate the in vitro anticancer efficacy of the ATR inhibitor berzosertib against canine hematopoietic cancer cell lines.
- To compare the cytotoxicity of berzosertib in cancer cells versus noncancerous canine cells.
- To investigate the potential synergistic effects of berzosertib with chlorambucil and its impact on DNA damage and apoptosis.
Main Methods:
- Cytotoxicity was assessed using MTT assays and flow cytometry across four canine lymphoma and leukemia cell lines.
- Apoptosis levels were quantified via flow cytometry, and DNA damage was evaluated by measuring H2AX phosphorylation using Western blot.
- Synergistic effects with chlorambucil and effects on cell cycle disturbances were analyzed using flow cytometry.
Main Results:
- Berzosertib exhibited significant anticancer activity against canine lymphoma and leukemia cells at concentrations non-toxic to normal canine cells, though sensitivity varied among cell lines.
- Cell death was mediated through caspase-dependent apoptosis, induced by DNA damage.
- Berzosertib demonstrated synergistic effects with chlorambucil, potentially by inhibiting DNA damage repair through abrogation of S-phase arrest.
Conclusions:
- ATR inhibition with berzosertib presents a potential novel therapeutic strategy for canine lymphomas and leukaemias.
- The drug effectively induces apoptosis and DNA damage in cancer cells, with varying sensitivity observed.
- Further research is warranted to identify biomarkers predicting susceptibility to ATR inhibition in canine cancers.
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