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Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
Published on: June 9, 2017
Modulation of DNA damage response by targeting ATM kinase using newly synthesized di-phenoxy acetamide (DPA) analogs
Fares Hezam Al-Ostoot1,2, Ankith Sherapura3, Vikas H Malojirao3,4
1Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, India.
Background:
Imbalance and instability in the structure of the DNA have become major characteristics of cancer. In response to DNA damage, DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), plays a pivotal role in the modulation of regulatory regions responsible for inhibition of apoptosis, thereby neoplastic progression.
Methods:
A new series of DPA (7a-t) were synthesized, characterized. Anti-proliferative studies to identify the lead compound were carried out by LDH and MTT assay. Apoptosis/DNA damage was measured through FACS, Annexin-v staining, TUNEL and Comet assay. Elucidation of molecular mechanism through immunoblot and further validation of the drug effect through in vivo approaches.
Results:
Initial in vitro anti-proliferative screening of Compounds DPA (7a-t) against multiple cancer cell lines identified Compound DPA (7n) as a potent cytotoxic molecule with IC50 value of 4.3 μM. Down the line, in vitro and in vivo evaluation of Compound DPA (7n) inferred that it has apoptotic inducing potentiality. Further, evaluation of molecular mechanism inferred that Compound DPA (7n) effectively modulates ATM phosphorylation only, eventually altering downstream signalling pathways.
Conclusions:
Compound DPA (7n) emerged as a potent proapoptotic and anti-neoplastic agent by inhibiting ATM kinase activity both in vitro and in vivo. The conferring results ascertain that the drug could be developed as a new ATM kinase inhibitor with anti-cancer capacity.
Insights
A new compound, DPA (7n), effectively induces apoptosis and inhibits cancer cell growth by targeting ATM kinase. This discovery presents a promising new ATM kinase inhibitor for anti-cancer therapy.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- DNA damage and instability are hallmarks of cancer.
- The DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), regulates apoptosis and neoplastic progression.
Purpose of the Study:
- To synthesize and evaluate novel DPA compounds for anti-cancer activity.
- To identify a lead compound that inhibits cancer cell proliferation and induces apoptosis.
- To elucidate the molecular mechanism of action of the lead compound.
Main Methods:
- Synthesis and characterization of DPA compounds (7a-t).
- In vitro anti-proliferative assays (LDH, MTT) and apoptosis/DNA damage assessments (FACS, Annexin-v, TUNEL, Comet assay).
- Molecular mechanism elucidation via immunoblotting and in vivo validation.
Main Results:
- Compound DPA (7n) demonstrated potent cytotoxicity against cancer cell lines (IC50 = 4.3 μM).
- DPA (7n) induces apoptosis and DNA damage in vitro and in vivo.
- DPA (7n) selectively modulates ATM phosphorylation, impacting downstream signaling.
Conclusions:
- Compound DPA (7n) is a potent proapoptotic and anti-neoplastic agent.
- DPA (7n) functions by inhibiting ATM kinase activity.
- DPA (7n) holds potential as a novel ATM kinase inhibitor for cancer treatment.
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