Editor's ChoiceChemotherapy and Infertility

Follicular Family

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Science Translational Medicine  07 Oct 2009:
Vol. 1, Issue 1, pp. 1ec3
DOI: 10.1126/scitranslmed.3000436

A devastating side effect of cancer chemotherapy in young women is failure of the ovaries, which can prevent subsequent pregnancies or, at best, heighten the risk of developmental defects. Damage to ovarian follicles results when stress pathways are activated in cells bombarded with chemotherapeutic genotoxins, such as cisplatin, ultimately leading to cell-cycle arrest or cell death. Despite its importance for younger patients faced with cancer, this phenomenon is not well understood, and ways to ameliorate the process have not been clearly identified. Stefania Gonfloni et al. investigated the loss of follicles in mouse ovaries upon systemic treatment with cisplatin. They found that follicular reserves can be protected by the inhibition of a pathway that activates the tyrosine kinase c-Abl and causes accumulation of p63, a homolog of the transcription factor p53. The activation of these master regulatory proteins that mediate cellular responses to stress often causes the cell to stop dividing in order to repair damage or to undergo cell death when such damage is irreparable. In this work, imatinib (Gleevec), a potent inhibitor of the c-Abl tyrosine kinase that was first identified for the treatment of chronic myelogenous leukemia, showed promise for protecting mouse oocytes from cisplatin-induced damage in vivo. Moreover, in human cell lines engineered to express p63, the authors showed that the kinase activity of c-Abl was necessary for the cisplatin-induced increase in p63 and that this accumulation was associated with activation of the downstream apoptotic genes NOXA and PUMA. In vitro treatment of these cells with imatinib prevented cisplatin-promoted p63 accumulation and cell death, recapitulating the phenotype observed in mouse oocytes. Although it remains unclear whether treatment with imatinib interferes with the tumor-killing effects of cisplatin, the possibility that imatinib may preserve fertility in young cancer patients undergoing treatment warrants further clinical investigation.

S. Gonfloni et al., Inhibition of the c-Abl–TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nat. Med. 27 September 2009 | doi:10.1038/nm.2033 http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2033.html

Citation: L. Khidr, Follicular Family, Sci. Transl. Med. 1, 1ec3 (2009).

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