Chemotherapy regimens based on cyclophosphamide (CPM) severely impacts fertility in women. CPM activates a damage response that suggests the involvement of oxidative stress (OS). In the ovary, this drug stimulates activation and premature loss of follicle reserve by activating PI3K/PTEN/AKT pathway throughout phosphorylation and inhibition of FOXO3a (Roness et al., 2014). In female germ cells, FOXO3a is also a component of an OS adaptive response under SIRT1 control (Di Emidio et al., 2014). This work investigates whether oral administration of saffronderived crocetin, a carotenoid with antioxidant and antitumor properties, affects ovarian early response to CPM and prevents gonadotoxicity in female mice. Eighteen CD1 female mice received a single intraperitoneal injection of PBS (CTRL), or CPM (100mg/kg) or crocetin (100mg/Kg) per os for fifteen days prior to CPM. We found that follicle loss in CPMmice assessed at 7 days postCPM was associated with an early increase of SIRT1 expression along with decrease of mitochondrial superoxide dismutase (SOD2) and mitochondrial biogenesis activator PGC1alpha at 24 hr postCPM. Crocetin administration significantly decreased CPMinduced follicles loss and prevented early CPMdamage response. In crocetin+CPM mice, the pattern of expression of pFOXO3a, pAKT and SIRT1 were similar to control mice and increased levels of SOD2 and PGC1alpha were observed suggesting that modulation of redox balance may help the ovary counteracting ovarian damage by CPM. Our results increase the knowledge of mechanisms underlying ovarian damage by CPM and will be helpful to develop new therapeutic opportunities.
Modulation of early ovarian response to cyclophosphamide damage alleviates gonadotoxicity in female mice: evidence for beneficial effects of saffron- derived crocetin
ROSSI, GIULIA;
2016-01-01
Abstract
Chemotherapy regimens based on cyclophosphamide (CPM) severely impacts fertility in women. CPM activates a damage response that suggests the involvement of oxidative stress (OS). In the ovary, this drug stimulates activation and premature loss of follicle reserve by activating PI3K/PTEN/AKT pathway throughout phosphorylation and inhibition of FOXO3a (Roness et al., 2014). In female germ cells, FOXO3a is also a component of an OS adaptive response under SIRT1 control (Di Emidio et al., 2014). This work investigates whether oral administration of saffronderived crocetin, a carotenoid with antioxidant and antitumor properties, affects ovarian early response to CPM and prevents gonadotoxicity in female mice. Eighteen CD1 female mice received a single intraperitoneal injection of PBS (CTRL), or CPM (100mg/kg) or crocetin (100mg/Kg) per os for fifteen days prior to CPM. We found that follicle loss in CPMmice assessed at 7 days postCPM was associated with an early increase of SIRT1 expression along with decrease of mitochondrial superoxide dismutase (SOD2) and mitochondrial biogenesis activator PGC1alpha at 24 hr postCPM. Crocetin administration significantly decreased CPMinduced follicles loss and prevented early CPMdamage response. In crocetin+CPM mice, the pattern of expression of pFOXO3a, pAKT and SIRT1 were similar to control mice and increased levels of SOD2 and PGC1alpha were observed suggesting that modulation of redox balance may help the ovary counteracting ovarian damage by CPM. Our results increase the knowledge of mechanisms underlying ovarian damage by CPM and will be helpful to develop new therapeutic opportunities.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
