Protective effects of a SIRT1 inhibitor on primordial follicle activation and growth induced by cyclophosphamide: insights from a bovine in vitro folliculogenesis system

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Abstract

Purpose

Although oncological advances have improved survival rates of female cancer patients, they often suffer a reduced fertility due to treatment side effects. In the present study, we evaluated the potential fertoprotective effects of the specific inhibitor of SIRT1, EX-527, on the gonadotoxic action exerted by cyclophosphamide (CPM) on loss of primordial follicles (PFs).

Methods

The effects of the CPM metabolite phosphoramide mustard (PM) on follicle activation, growth and viability and the protective action of EX-527 against PM effects were evaluated on bovine ovarian cortical strips in vitro cultured for 1 or 6 days. To understand whether PFs exposed to PM plus EX-527 were able to activate and grow to the secondary stage after suspension of the treatment, strips cultured for 3 days in PM plus EX-527 for 3 days were transferred to plain medium until day 6. Follicle growth and health were evaluated through histology and viability assay at a confocal microscope. In order to investigate the molecular pathways underlying the ovarian response to PM in the presence of EX-527, we analysed the protein level of SIRT1, HuR, PARP1 and SOD2 after 1 day of in vitro culture.

Results

We found that (1) PM, the main CPM active metabolite, promotes PF activation; (2) the ovarian stress response induced by PM includes a SIRT1-dependent pathway; and (3) EX-527 reduces PF activation and growth induced by PM.

Conclusion

SIRT1 can represent a candidate molecule to be targeted to protect ovarian follicles from alkylating agents and EX-527 could represent a potential fertoprotective agent for cancer patients.

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Most cited references 55

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Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.

Mark Robson, Seock-Ah Im, Elżbieta Senkus … (2017)

Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation.

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SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction.

Meng-Tsen Ke, Satoshi Fujimoto, Takeshi Imai (2013)

We report a water-based optical clearing agent, SeeDB, which clears fixed brain samples in a few days without quenching many types of fluorescent dyes, including fluorescent proteins and lipophilic neuronal tracers. Our method maintained a constant sample volume during the clearing procedure, an important factor for keeping cellular morphology intact, and facilitated the quantitative reconstruction of neuronal circuits. Combined with two-photon microscopy and an optimized objective lens, we were able to image the mouse brain from the dorsal to the ventral side. We used SeeDB to describe the near-complete wiring diagram of sister mitral cells associated with a common glomerulus in the mouse olfactory bulb. We found the diversity of dendrite wiring patterns among sister mitral cells, and our results provide an anatomical basis for non-redundant odor coding by these neurons. Our simple and efficient method is useful for imaging intact morphological architecture at large scales in both the adult and developing brains.

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Is Open Access

Ovarian damage from chemotherapy and current approaches to its protection

N Spears, F. Lopes, A Stefánsdóttir … (2019)

Abstract Background Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage. Objective and rationale This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed. Search methods Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents. Outcomes Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed. Wider implications Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically.

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Author and article information

Contributors

Carla Tatone:

ORCID: http://orcid.org/0000-0002-4978-2571

carla.tatone@univaq.it

Journal

Journal ID (nlm-ta): J Assist Reprod Genet

Journal ID (iso-abbrev): J Assist Reprod Genet

Title: Journal of Assisted Reproduction and Genetics

Publisher: Springer US (New York )

ISSN (Print): 1058-0468

ISSN (Electronic): 1573-7330

Publication date (Electronic): 5 March 2022

Publication date PMC-release: 5 March 2022

Publication date (Print): April 2022

Volume: 39

Issue: 4

Pages: 933-943

Affiliations

[1 ]GRID grid.158820.6, ISNI 0000 0004 1757 2611, Department of Life, Health and Environmental Sciences, , University of L’Aquila, ; Building Delta 6, Via G. Petrini 6, 67100 L’Aquila, Italy

[2 ]GRID grid.4691.a, ISNI 0000 0001 0790 385X, Dipartimento di Biologia, , Università di Napoli “Federico II”, Complesso Universitario di Monte S Angelo, ; Via Cinthia, 80126 Naples, Italy

Author information

Giovanna Di Emidio http://orcid.org/0000-0001-9442-6923

Carla Tatone http://orcid.org/0000-0002-4978-2571

Martina Placidi http://orcid.org/0000-0002-4893-932X

Riccardo Talevi http://orcid.org/0000-0003-3767-5258

Roberto Gualtieri http://orcid.org/0000-0002-0424-5254

Article

Publisher ID: 2437

DOI: 10.1007/s10815-022-02437-9

PMC ID: 9051010

PubMed ID: 35247119

SO-VID: 9be00408-af50-43b4-a84a-d15223314325

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 30 November 2021

Date accepted : 13 February 2022

Funding

Funded by: University of L'Aquila

Funded by: San Salvatore Hospital, L'Aquila, Italy

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: ex-527,sirt1,hur,in vitro folliculogenesis,fertoprotective agents,cyclophosphamide

Data availability:

ScienceOpen disciplines: Genetics

Keywords: ex-527, sirt1, hur, in vitro folliculogenesis, fertoprotective agents, cyclophosphamide

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Protective effects of a SIRT1 inhibitor on primordial follicle activation and growth induced by cyclophosphamide: insights from a bovine in vitro folliculogenesis system

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Most cited references 55

Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.

SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction.

Ovarian damage from chemotherapy and current approaches to its protection

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