Phosphoramide mustard induces autophagy markers and mTOR inhibition prevents follicle loss due to phosphoramide mustard exposure

Madden, Jill A.; Thomas, Porsha Q.; Keating, Aileen F.

doi:10.1016/j.reprotox.2016.11.014

Cited by 15 publications

(13 citation statements)

References 85 publications

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“…Different numbers of growing follicles post-PM treatment were not observed, suggesting lack of hyperactivation of the ovarian reserve. This corresponded with our previous findings in which inhibition of PI3K did not have any effect on the extent of PM-induced follicle loss [48]. The Atm +/mice had reduced follicle number at all stages of development, highlighting the importance of ATM in basal ovarian physiology and recapitulating phenotypic observations in A-T female patients [9].…”

Section: Discussionsupporting

confidence: 90%

Ataxia–telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard

Clark

Keating

2019

Biology of Reproduction

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Ataxia–telangiectasia-mutated (ATM) protein recognizes and repairs DNA double strand breaks through activation of cell cycle checkpoints and DNA repair proteins. Atm gene mutations increase female reproductive cancer risk. Phosphoramide mustard (PM) induces ovarian DNA damage and destroys primordial follicles, and pharmacological ATM inhibition prevents PM-induced follicular depletion. Wild-type (WT) C57BL/6 or Atm+/− mice were dosed once intraperitoneally with sesame oil (95%) or PM (25 mg/kg) in the proestrus phase of the estrous cycle and ovaries harvested 3 days thereafter. Atm+/− mice spent ~25% more time in diestrus phase than WT. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) on ovarian protein was performed and bioinformatically analyzed. Relative to WT, Atm+/− mice had 64 and 243 proteins increased or decreased in abundance, respectively. In WT mice, PM increased 162 and decreased 20 proteins. In Atm+/− mice, 173 and 37 proteins were increased and decreased, respectively, by PM. Exportin-2 (XPO2) was localized to granulosa cells of all follicle stages and was 7.2-fold greater in Atm+/− than WT mice. Cytoplasmic FMR1-interacting protein 1 was 6.8-fold lower in Atm+/− mice and was located in the surface epithelium with apparent translocation to the ovarian medulla post-PM exposure. PM induced γH2AX, but fewer γH2AX-positive foci were identified in Atm+/− ovaries. Similarly, cleaved caspase-3 was lower in the Atm+/− PM-treated, relative to WT mice. These findings support ATM involvement in ovarian DNA repair and suggest that ATM functions to regulate ovarian atresia.

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Section: Discussionsupporting

confidence: 90%

Ataxia–telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard

Clark

Keating

2019

Biology of Reproduction

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“…The mechanisms behind primordial follicle loss induced by chemotherapy have been extensively investigated, but they remain largely unclear [20,21,22,23,24,25,26,27,28,29]. The reported mechanisms include a primary or a secondary effect on the primordial follicles resulting in depletion of the ovarian reserve.…”

Section: Chemotherapy-induced Ovarian Damagementioning

confidence: 99%

“…As their primary effect (Figure 4), chemotherapeutic agents can directly induce DNA damage (e.g. double-strand breaks (DSBs), inter- and intra-strand crosslinks, intercalation, and monoalkylation), which results in the activation of apoptosis and/or autophagy-related pathways [20,22,23,24,27], or they can indirectly cause DNA damage by increasing oxidative stress or by damaging the ovarian micro-vessel network, leading to cellular stress such as ischemia and nutrient deprivation [28,29]. In addition, it has also been proposed that dormant primordial follicles can be overactivated as a secondary effect.…”

Section: Chemotherapy-induced Ovarian Damagementioning

confidence: 99%

“…Cultured rat ovaries exposed to PM showed abnormally large Golgi apparatuses and electron-dense mitochondria by transmission election microscopy. Increases in the autophagy-related protein BECN1 and in lysosome-associated membrane protein have also been detected after PM exposure [27]. However, more research is needed to clearly identify all steps involved in the autophagy pathway.…”

Section: Chemotherapy-induced Ovarian Damagementioning

confidence: 99%

“…In order to develop such protective treatments, the mechanisms behind how chemotherapy damages the ovary have to be better understood. Many of the mechanisms involved remain unclear [20,21,22,23,24,25,26,27,28,29], but the two main theories that dominate this research field are that POF is the result of the induction of DNA damage and/or oxidative stress in the follicles that triggers apoptosis [21,22] or is the result of overactivation of the dormant primordial follicles [25,26]. Most of the research on these damaging mechanisms has been performed in experimental animal models, and the translation to clinical treatments might take years.…”

Section: Introductionmentioning

confidence: 99%

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Ovarian Follicle Depletion Induced by Chemotherapy and the Investigational Stages of Potential Fertility-Protective Treatments—A Review

Hao

Anastácio

Liu

et al. 2019

IJMS

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Ovarian follicle pool depletion, infertility, and premature menopause are all known sequelae of cancer treatment that negatively impact the quality of life of young cancer survivors. The mechanisms involved in this undesired iatrogenic ovarian damage have been intensively studied, but many of them remain unclear. Several chemotherapeutic drugs have been shown to induce direct and indirect DNA-damage and/or cellular stress, which are often followed by apoptosis and/or autophagy. Damage to the ovarian micro-vessel network induced by chemotherapeutic agents also seems to contribute to ovarian dysfunction. Another proposed mechanism behind ovarian follicle pool depletion is the overactivation of primordial follicles from the quiescent pool; however, current experimental data are inconsistent regarding these effects. There is great interest in characterizing the mechanisms involved in ovarian damage because this might lead to the identification of potentially protective substances as possible future therapeutics. Research in this field is still at an experimental stage, and further investigations are needed to develop effective and individualized treatments for clinical application. This review provides an overview of the current knowledge and the proposed hypothesis behind chemotherapy-induced ovarian damage, as well as current knowledge on possible co-treatments that might protect the ovary and the follicles from such damages.

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Chemotherapeutic drugs induced female reproductive toxicity and treatment strategies

Bhardwaj

Bikal

Sachdeva

2023

J Biochem & Molecular Tox

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Increase in success of cancer treatment with advancement in the screening, prognosis and diagnosis protocols have significantly improved the rate of cancer survivorship. With the declining cancer mortality, however, the cancer survivors are also subjected to the adverse consequences of chemotherapy, particularly in the female reproductive system. Recent studies have shown the sensitivity of the ovarian tissue to the chemotherapeutic drugs‐induced toxicity. Several in vitro and in vivo studies have assessed the toxic effects of chemotherapeutic drugs. The most frequently used chemotherapeutic drugs such as doxorubicin, cyclophosphamide, cisplatin and paclitaxel have been reported to cause ovarian damage, diminution of follicular pool reserve, premature ovarian failure and early menopause, resulting into declining fertility potential among females. The chemotherapy often employs combination of drug regimen to increase the efficacy of the treatment. However, the literature mostly consists of clinical data regarding the gonadotoxicity caused by anticancer drugs but there lacks the understanding of toxicity mechanism. Therefore, understanding of the different toxicity mechanisms will be helpful in development of possible therapeutic interventions for preservation of declining female fertility among cancer survivors. The current review comprehends the underlying mechanisms of female reproductive toxicity induced by the most commonly used chemotherapeutic drugs. In addition, the review also summarizes the recent findings related to the use of various protectants to diminish or at least in managing the toxicity induced by different chemotherapeutic drugs in females.

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Phosphoramide mustard induces autophagy markers and mTOR inhibition prevents follicle loss due to phosphoramide mustard exposure

Cited by 15 publications

References 85 publications

Ataxia–telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard

Ataxia–telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard

Ovarian Follicle Depletion Induced by Chemotherapy and the Investigational Stages of Potential Fertility-Protective Treatments—A Review

Chemotherapeutic drugs induced female reproductive toxicity and treatment strategies

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