Article Sidebar
Views PDF: 39
DNA-DEPENDENT PROTEIN KINASE INHIBITOR INDUCES APOPTOSIS IN COLON CANCER CELLS
Main Article Content
Abstract
Objectives: Among all types of DNA damage, DNA double-strand breaks (DSBs) are considered the most deleterious form induced by either endogenous factors (oxi-dative damages, mismatches, altered chromatin structures, and missing, or modified nucleotides) or exogenous factors, i.e., ultraviolet (UV) radiation, ionizing radiation (IR), and chemicals or drugs. DNA-dependent protein kinase (DNA-PK) plays a crucial role in repairing DSBs through non-homologous end joining (NHEJ). Cells lacking DNA-PK exhibit heightened sensitivity to IR and various DNA-damaging agents. The inhibition of DNA-PK further intensifies cellular susceptibility to IR and DNA-damaging agents. Several small molecules that inhibit DNA-PK have been developed. This study aimed to evaluate the effect of DNA-PK inhibitor (DNA-PKi) NU7441 on the HCT116 cell line. Methods: DNA-PKi NU7441 was used to assess the effect on anti-proliferation and induction of apoptosis on the HCT116 colorectal cancer cell line. Cells were cultured under standard conditions; crystal violet and apoptosis assay were applied to evaluate cell proliferation and apoptosis. Data were analysed using GraphPad Prism 8.4. Results: DNA-PKi effectively inhibited HCT116 colon cancer cell growth via crystal violet assay (p < 0.01). In addition, DNA-PKi also induced programmed cell death in the HCT116 cell line (p < 0.05). Conclusion: DNA-PKi NU7441 suppressed cell proliferation and induced apoptosis in the HCT116 colon cancer cell line.
Article Details
Keywords
DNA-PK, DNA-PKi, DNA damage repair, Non-homologous end joining, Colon cancer
References
2. Y Matsumoto. Development and evolution of DNA-Dependent Protein kinase inhibitors toward cancer therapy. Int. J. Mol. Sci. Jan 2022; 23(8). DOI: 10.3390/ijms23084264.
3. Double-stranded DNA induces the phosphorylation of several proteins including the 90 000 mol. wt. heat-shock protein in animal cell extracts. Accessed: Jan. 17, 2024. [Online]. Available: https://www.embopress.org/doi/epdf/10.1002/j.1460-2075.1985.tb02328.x.
4. BL Ruis, KR Fattah, and EA Hendrickson. The catalytic subunit of DNA-dependent protein kinase regulates proliferation. Telomere length, and genomic stability in human somatic cells. Mol. Cell. Biol. Oct 2008; 28(20):6182-6195. DOI: 10.1128/MCB. 00355-08.
5. JM Sekiguchi and DO Ferguson. DNA Double-strand break repair: A relentless hunt uncovers new prey. Cell. Jan 2006; 124(2):260-262. DOI: 10.1016/j.cell.2006.01.010.
6. M O’Driscoll et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol. Cell. Dec 2001; 8(6):1175-1185. DOI: 10.1016/S1097-2765(01)00408-7.
7. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient - ScienceDirect. Accessed: Jan. 17, 2024. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S096098229980311X.
8. D Moshous et al. Artemis, a Novel DNA Double-Strand Break Repair/V(D)J recombination protein, is mutated in human with severe combined immune deficiency. Cell. Apr 2001; 105(2):177-186. DOI: 10.1016/S0092-8674(01)00309-9.
9. A Cardinale et al. DNA repair protein DNA-PK protects PC12 cells from oxidative stress-induced apoptosis involving AKT phosphorylation. Mol Biol Rep. Feb 2022; 49(2):1089-1101. DOI: 10.1007/s11033-021-06934-5.
10. Y Zhao et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. May 2006; 66(10):5354-5362. DOI: 10.1158/ 0008-5472.CAN-05-4275.