The Natural Carotenoid Crocetin and the Synthetic Tellurium Compound AS101 Protect the Ovary against Cyclophosphamide by Modulating SIRT1 and Mitochondrial Markers

Abstract

Cancer therapies are associated with increased infertility risk due to accelerated reproductive aging. Oxidative stress (OS) is a potential mechanism behind ovarian toxicity by cyclophosphamide (CPM), the most ovotoxic anticancer drug. An important sensor of OS is SIRT1, a NAD+-dependent deacetylase which regulates cellular defence and cell fate. This study investigated whether the natural carotenoid crocetin and the synthetic compound AS101 protect the ovary against CPM by modulating SIRT1 and mitochondrial markers. We found that the number of primordial follicles of female CD1 mice receiving crocetin plus CPM increased when compared with CPM alone and similar to AS101, whose protective effects are known. SIRT1 increased in CPM mouse ovaries revealing the occurrence of OS. Similarly, mitochondrial SIRT3 rose, whilst SOD2 and the mitochondrial biogenesis activator PGC1-α decreased, suggesting the occurrence of mitochondrial damage. Crocetin and AS101 administration prevented SIRT1 burst suggesting that preservation of redox balance can help the ovary to counteract ovarian damage by CPM. Decreased SIRT3 and increased SOD2 and PGC1-α in mice receiving crocetin or AS101 prior to CPM provide evidence for mitochondrial protection. Present results improve the knowledge of ovarian damage by CPM and may help to develop interventions for preserving fertility in cancer patients.

Crocetin Mitigates Irradiation Injury in an In Vitro Model of the Pubertal Testis: Focus on Biological Effects and Molecular Mechanisms

“…In contrast to SOD2, CAT levels were reduced in the irradiated sample, revealing an altered process of mitochondrial detoxification of the superoxide anion, resulting in a condition of oxidative stress. The observation that crocetin exposure was effective in maintaining basal protein levels of SOD2 and CAT during IR supports the hypothesis that radioprotective activity of crocetin is mediated by its ROS scavenging activity or modulation of antioxidants genes [ 31 , 48 , 50 , 51 , 52 ]. A further evidence is the observation in testes cultured in the presence of crocetin prior and after irradiation of a reduction of oxidative damage measured by levels of 4-HNE, a well-known marker of lipid peroxidation [ 42 ].…”

“…In the present study, we investigated the hypothesis that crocetin may exert a radioprotective effect by preventing IR-induced damage in testis of pubertal mice. This hypothesis is based on the knowledge of the potent anti-tumor effects of this molecule, a feature essential for a potential fertoprotective agent, and on its ability to prevent ovarian toxicity induced by cyclophosphamide, an anticancer drug with strong pro-oxidant power [ 31 ]. In this study, we utilized an in vitro culture system of prepubertal mouse testes as an experimental model of spermatogenesis to investigate the efficacy of crocetin to counteract X-ray-induced testicular injury and the mechanisms underlying IR insult and potential crocetin effects.…”

Ovarian damage from chemotherapy and current approaches to its protection

“…An inflammation response has been shown through increased levels of the pro-inflammatory cytokines IL-6 and -8 and TNFα alongside reduced levels of the anti-inflammatory IL-10, although this was in response to administration of both CPM and busulfan (Luo et al., 2017). CPM also leads, in mouse oocytes, to an increase in the expression of the cell redox state sensor SIRT1, as the result of the adaptive response to oxidative stress (Di Emidio et al., 2017). In fact, SIRT1 is involved in both inflammation and oxidative stress, by inhibiting NF-kB signalling and stimulating the expression of antioxidants through FoxO transcription factors, respectively (Xie et al.…”

“…Crocetin can also provide protection against toxicant-induced oxidative stress along with underlying disorders in numerous organs, tissues and cells (Xi et al., 2007). Crocetin administration (as with AS101) prevents an increase in SIRT1 expression, suggesting that preservation of the redox balance can help the ovary counteract CPM-induced ovarian damage (Di Emidio et al., 2017). Despite this, crocetin and AS101 were not able to fully counteract effects on oocyte imprinting in offspring (Di Emidio et al., 2019).…”

The Role of Oxidative Stress and Natural Antioxidants in Ovarian Aging

“…In addition, crocetin administration reduces follicle loss and rescues fertility in CPM-treated mice. Mechanistically, crocetin protects the ovary against CPM by modulating redox balance, decreasing SIRT3, and increasing the antioxidant enzyme, SOD2, as well as the mitochondrial biogenesis activator, PGC1α ( Di Emidio et al, 2017 ).…”