Primary liver cancer, which consists of predominantly hepatocellular carcinoma (HCC), is the fifth most common cancer worldwide and the third most common cause of cancer mortality. The majority of patients are diagnosed with advanced disease when only palliative therapies are an option. HCC are notoriously resistant to chemotherapies. Several key DNA damage signalling and repair genes were significantly up-regulated in HCC. Most marked was the up-regulation in line with progression, of the PRKDC gene, the product of which is DNA-PKcs, the key enzyme which orchestrates the non-homologous end joining pathway of DNA double strand break repair. Increased PRKDC expression was also observed in non-alcoholic fatty liver disease, increasing with degree of inflammation, implicating DNA-PK in the pathogenesis of chronic liver disease, HCC, and possibly chemotherapy resistance. Inhibition of DNA-PK by NU7441 caused substantial retardation of early, NHEJ-mediated, DSB signalling and repair, and increased dependence on homologous recombination in HCC cell lines. NU7441 also significantly potentiated ionizing radiation and doxorubicin induced cytotoxicity, causing a dramatic decrease in cell growth and survival. Furthermore, whilst ATM inhibition by KU55933 or DNA-PK inhibition by NU7441 alone had no effect on cell survival, the combination was cytotoxic to all HCC cell lines used. DNA-PK protein levels and activity were substantially higher in HCC tumour tissues than non-tumour liver tissue, and further increased with tumour grade. Increased tumour DNAPK levels were associated with reduced time to progression and poorer survival in patients following transarterial chemoembolization with DNA-damaging agent, doxorubicin. Also, DNA-PK activity was an independent predictor of survival in a cohort of 44 HCC patients. These data suggest patients with high DNA-PK protein levels and/or activity may benefit from the inclusion of a DNA-PK inhibitor either alone, in combination with a DNA-damaging agent such as doxorubicin, or in combination with an ATM inhibitor.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:613438 |
| Date | January 2012 |
| Creators | Cornell, Liam |
| Publisher | University of Newcastle Upon Tyne |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
Page generated in 0.0065 seconds