Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation

Eldani, Maya; Luan, Yi; Xu, Pauline; Bargar, Tom W.; Kim, Sang Hyun

doi:10.1096/fj.202001461rr

Cited by 17 publications

(20 citation statements)

References 44 publications

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“…S1). This indicates that follicle hyperactivation is not the major mechanism of PMF loss in prepubertal ovaries or ex vivo explants and is in agreement with other studies (35,47,48). It is possible that MAFO (an analog of CTX) has a different effect on ovaries ex vivo than CTX in vivo, however both drugs have been shown to generate similar metabolites (37,42).…”

Section: Figure 1 Chek2 Deficiency Prevents Primordial Oocyte Depletion After Ex Vivo Treatment With Mafo Cddp Dox and Etosupporting

confidence: 89%

Chek2 Signaling Is the Key Regulator of Oocyte Survival After Chemotherapy

Emori

Boucher

Bolcun-Filas

2021

Preprint

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Radiation and chemotherapy can damage the primordial follicle reserve in female cancer patients leading to ovarian failure and infertility. Preservation of ovarian function requires treatment strategies that prevent loss of immature oocytes in primordial follicles during cancer therapy. Checkpoint kinase 2 (CHEK2) inhibition prevents loss of primordial oocytes caused by DNA damage and thus is a promising target for ovoprotective treatment against genotoxic agents. To determine which cancer treatments could benefit from ovoprotective activity of CHEK2 inhibition we investigated oocyte survival in Chek2-/- mice exposed to different chemotherapy drugs. Here, we show that loss of CHEK2 function prevents elimination of primordial oocytes damaged by cisplatin, cyclophosphamide, mafosfamide, doxorubicin, and etoposide, suggesting it could be used to reduce ovarian damage caused by wide range of drugs. Using genetic knockouts we reveal a critical role for TRP53 in oocyte response to chemotherapy drugs and show that both targets of CHEK2, TAp63 and TRP53, are activated by cisplatin and cyclophosphamide. Furthermore, we show that checkpoint kinase inhibitor and radiation- and chemotherapy sensitizer AZD7762 reduces oocyte elimination after radiation and chemotherapy treatments, despite its cytotoxic effect on ovarian somatic cells. Altogether, these findings demonstrate the role for CHEK2 as the master regulator of primordial oocyte survival or death and credential its targeting for ovoprotective treatments.

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Section: Figure 1 Chek2 Deficiency Prevents Primordial Oocyte Depletion After Ex Vivo Treatment With Mafo Cddp Dox and Etosupporting

confidence: 89%

Chek2 Signaling Is the Key Regulator of Oocyte Survival After Chemotherapy

Emori

Boucher

Bolcun-Filas

2021

Preprint

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“…It has been suggested that CPA can induce a unique death pathway in the oocytes of primordial follicles that differs from CDDP or radiation ( 10 – 12 , 18 , 23 ). To investigate the pathway triggered by CPA in oocytes, intensities of γH2AX, a DNA damage marker, and p-CHK2, a DNA damage responder, were measured in a timely manner.…”

Section: Resultsmentioning

confidence: 99%

“…Transmission electron microscopy PD5 CD-1 female mice were injected once with solvent, CDDP (5 mg/kg), DOXO (7.5 mg/kg), and CPA (150 mg/kg) for 18 hours of treatment, followed by further TEM steps. The preparation of ovarian sections was performed as previously described (23). Sections were examined on an FEI Tecnai G2 TEM operated at 80 kV after staining with 1% uranyl acetate and Reynold's lead citrate.…”

Section: Immunoblottingmentioning

confidence: 99%

TAp63 determines the fate of oocytes against DNA damage

Luan

Abazarikia

et al. 2022

Sci. Adv.

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Cyclophosphamide and doxorubicin lead to premature ovarian insufficiency as an off-target effect. However, their oocyte death pathway has been debated. Here, we clarified the precise mechanism of ovarian depletion induced by cyclophosphamide and doxorubicin. Dormant oocytes instead of activated oocytes with high PI3K activity were more sensitive to cyclophosphamide. Checkpoint kinase 2 (CHK2) inhibitor rather than GNF2 protected oocytes from cyclophosphamide and doxorubicin, as cyclophosphamide up-regulated p-CHK2 and depleted primordial follicles in Abl1 knockout mice. Contrary to previous reports, TAp63 is pivotal in cyclophosphamide and doxorubicin-induced oocyte death. Oocyte-specific Trp63 knockout mice prevented primordial follicle loss and maintained reproductive function from cyclophosphamide and doxorubicin, indicated by undetectable levels of BAX and cPARP. Here, we demonstrated that TAp63 is fundamental in determining the signaling of oocyte death against DNA damage. This study establishes the role of TAp63 as a target molecule of adjuvant therapies to protect the ovarian reserve from different classes of chemotherapy.

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“…Table 1 shows cisplatin protocols in mice reported in publications in 2020/2021. Nephrotoxicity [42][43][44] was by far the most frequently studied toxicity, followed by neurotoxicity [45][46][47], ototoxicity [16,48,49], gonadotoxicity [50][51][52][53], gastrointestinal toxicity [54][55][56], muscle wasting [57][58][59] and anemia [60]. A MEDILINE/PubMed search, using keywords "cisplatin","mouse","toxicity" was conducted in February 2021.…”

Section: Cisplatin Mouse Modelsmentioning

confidence: 99%

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

Perše

2021

Biomedicines

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Cisplatin is one of the most widely used chemotherapeutic drugs in the treatment of a wide range of pediatric and adult malignances. However, it has various side effects which limit its use. Cisplatin mouse models are widely used in studies investigating cisplatin therapeutic and toxic effects. However, despite numerous promising results, no significant improvement in treatment outcome has been achieved in humans. There are many drawbacks in the currently used cisplatin protocols in mice. In the paper, the most characterized cisplatin protocols are summarized together with weaknesses that need to be improved in future studies, including hydration and supportive care. As demonstrated, mice respond to cisplatin treatment in similar ways to humans. The paper thus aims to illustrate the complexity of cisplatin side effects (nephrotoxicity, gastrointestinal toxicity, neurotoxicity, ototoxicity and myelotoxicity) and the interconnectedness and interdependence of pathomechanisms among tissues and organs in a dose- and time-dependent manner. The paper offers knowledge that can help design future studies more efficiently and interpret study outcomes more critically. If we want to understand molecular mechanisms and find therapeutic agents that would have a potential benefit in clinics, we need to change our approach and start to treat animals as patients and not as tools.

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Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation

Cited by 17 publications

References 44 publications

Chek2 Signaling Is the Key Regulator of Oocyte Survival After Chemotherapy

Chek2 Signaling Is the Key Regulator of Oocyte Survival After Chemotherapy

TAp63 determines the fate of oocytes against DNA damage

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

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