Study On Mechanism Of ATN-224 Inhibiting Prostate Cancer Cell Growth Based On DNA Oxidative Damage

Prostate cancer is one of the most vulnerable genitourinary system disease among male,with a high morbidity and mortality only behind the ranked first lung cancer,it’s mortality among various cancer in male also come second.With the change of the environment and lifestyle and the aging of populations,the morbidity of prostate cancer in our country has shown an obvious upward trend.Notably,the oxidative stress is closely related with the occurrence and development of prostate cancer.Oxidative stress means the increase of reactive oxygen species in cells(such as H2O2,O2·-and·OH),which could break the balance between oxidative and antioxidative system,resulting internal environment disturbance and eventually lead to cancerization.SOD1 has an important role in eliminating reactive oxygen species and maintaining internal redox balance.ATN-224,a high-efficiency SOD1 inhibitor,has entered phase Ⅱ trial of prostate cancer treatment,though the antitumor mechanism about antiangiogenic is already quite explicit,the oxidative stress related anti prostate cancer mechanism is still not clear.We thus preliminary discussed the antitumor mechanism of ATN-224 in the following two aspects:1.ATN-224 selectively regulates the level of reactive oxygen species in prostate cancer cell and resulting DNA damageThrough the detection the level of O2·-,H2O2 and DNA damage,we found that ATN-224 can selectively cause O2·-and H2O2 level increased in prostate cancer cells DU 145,resulting DNA damage,but has not obvious influence on normal prostate cells RWPE1.At the same time,we found that ATN-224 can directly inhibit catalase activity which explains the reason of H2O2 increasement in DU145.2.ATN-224 promotes the relevant apoptosis signalThrough MTT,Sofe agar colony formation assay and cell cycle experiments,we found that ATN-224 can effectively inhibit DU 145 cells growth and arrest cell cycle at G1 period.The Annexin V-FITC/PI experiments confirmed that ATN-224 could selectivity promote apoptosis in DU 145 cells rather than RWPE-1 cells.Finally,the RT-PCR and western-blot experiments indicated the upward trend of tumor inhibiting gene p53 and DNA repair protein hOGG1 in DU145 and without apparent influence on RWPE1 cells,which further explain the reason why ATN-224 could selectively induce DU 145 cells apoptosis rather than RWPE1 cells.The full thesis,give a preliminary explain for the mechanism about the antitumor activity of a typical SOD1 inhibitor,ATN-224,to prostate cancer cells based on oxidative stress and apoptosis signal pathway study,which may provide a theoretical basis for the development of anti-prostate cancer drugs.