Abstract
Regardless of the achievable remissions with first line hormone therapy in patients with prostate cancer (CaP), the disease escapes the hormone dependent stage to a more aggressive status where chemotherapy is the only effective treatment and no treatment is curative. This makes it very important to identify new targets that can improve the outcome of treatment. ATM and DNA-PK are the two kinases responsible for signalling and repairing double strand breaks (DSB). Thus, both kinases are pertinent targets in CaP treatment to enhance the activity of the numerous DNA DSB inducing agents used in CaP treatment such as ionizing radiation (IR). Colony formation assay was used to assess the sensitivity of hormone dependent, p53 wt (LNCaP) and hormone independent p53 mutant (PC3) CaP cell lines to the cytotoxic effect of IR and Doxorubicin in the presence or absence of Ku55933 and NU7441 which are small molecule inhibitors of ATM and DNA-PK, respectively. Flow cytometry based methods were used to assess the effect of the two inhibitors on cell cycle, apoptosis and H2AX foci formation. Neutral comet assay was used to assess the induction of DNA DSBs. Ku55933 or NU7441 alone increased the sensitivity of CaP cell lines to the DNA damaging agents, however combining both inhibitors together resulted in further enhancement of sensitivity. The cell cycle profile of both cell lines was altered with increased cell death, DNA DSBs and H2AX foci formation. This study justifies further evaluation of the ATM and DNA-PK inhibitors for clinical application in CaP patients. Additionally, the augmented effect resulting from combining both inhibitors may have a significant implication for the treatment of CaP patients who have a defect in one of the two DSB repair pathways.
Highlights
According to the U.S National Institutes of Health, the ageadjusted incidence rate of prostate cancer 2003–2007 was 156.9 per 100.000 men per year
This study was designed as a preclinical evaluation of both Ataxia telangiectasia mutated (ATM) and DNA-PK inhibitors to investigate whether these inhibitors can improve the efficacy of DNA double strand break (DSB) inducing agents for CaP treatment
ionizing radiation (IR) induced DNA-PKSer2056 phosphorylation was inhibited by NU7441 and surprisingly doxorubicin induced DNA-PKSer2056 phosphoryla tion was inhibited by Ku55933
Summary
According to the U.S National Institutes of Health, the ageadjusted incidence rate of prostate cancer 2003–2007 was 156.9 per 100.000 men per year. High response rates can be achieved by first line therapy with surgery, radiotherapy, antiandrogen or their combinations; the natural progress of the disease is towards the hormone refractory status [1] where chemotherapy is the most effective treatment but still not curative [2]. This resistance highlights the importance of identifying new targets that can increase the sensitivity of CaP cells and the response rates and overall survival of patients. This study was designed as a preclinical evaluation of both ATM and DNA-PK inhibitors to investigate whether these inhibitors can improve the efficacy of DNA DSB inducing agents for CaP treatment
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