Premature ovarian insufficiency (POI) is a severe side effect of classical chemotherapy and radiotherapy in treatment of female cancer patients of reproductive age. The molecular mechanisms underlying POI are diverse, ranging from altered hormone levels to decimated resting oocyte reserve by apoptosis or elevated recruitment. The p53-homolog TAp63α emerged as the key protein regulating apoptosis following DNA damage in primary oocytes. In this study we monitored the ovotoxicity of widely used chemotherapeutic agents utilizing a GFP-c-Kit transgenic mouse model, the involvement of active TAp63α and the mechanism of action leading to its activation. Our studies show that alkylating agents as well as topoisomerase II poisons are potent activators of TAp63α by directly inducing DNA damage. Oxidative stress as well as DNA-intercalation were not sufficient to trigger TAp63α activation despite showing a strong general ovotoxicity. These results are in agreement with several previous investigations that have demonstrated that DNA double strand breaks are the most effective way to initiate apoptosis in primordial follicles. The widely used catalytic topoisomerase II inhibitor ICRF-187 were able to prevent doxorubicin-mediated activation of TAp63α by the topoisomerase II poisons doxorubicin
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Online ISSN: 1741-7899
Print ISSN: 1470-1626
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