Retrovirus-mediated multidrug resistance gene (MDR1) overexpression inhibits chemotherapy-induced toxicity of granulosa cells

Salih, Sana M.

doi:10.1016/j.fertnstert.2011.01.128

Cited by 9 publications

(5 citation statements)

References 40 publications

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“…Very few models of protection of the ovary from chemotherapy toxicity have been reported in the literature (Morita et al 2000, Perez et al 2007a,b, Yeh et al 2008, Gonfloni et al 2009, Salih 2011. In this context, one of the major compartments deserving such protection is represented by granulosa cells, which are mainly responsible for hormone production and thus follicular progression.…”

Section: Discussionmentioning

confidence: 99%

T3 preserves ovarian granulosa cells from chemotherapy-induced apoptosis

Falzacappa¹,

Timperi²,

Bucci³

et al. 2012

Journal of Endocrinology

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Infertility is a dramatic and frequent side effect in women who are undergoing chemotherapy. Actual strategies are mainly focused on oocyte cryopreservation, but this is not always a suitable option. Considering the key role that granulosa cells play in follicle life, we studied whether thyroid hormone 3,5,3 0 -triiodothyronine (T 3 ) protects rat ovarian granulosa cells from chemotherapy-induced apoptosis. To this aim, a cell line was established from fresh isolated rat granulosa cells and named rGROV. Cells were exposed to paclitaxel (PTX) and T 3 , and apoptosis, cell viability, and cell cycle distribution were analyzed under different conditions. First, the integrity of the steroidogenic pathway was demonstrated, and the presence of thyroid receptors, transporters, and deiodinases was confirmed by quantitative PCR. Cells were then exposed to PTX alone or contemporary to T 3 . MTT and TUNEL assays revealed that while there was a relevant percentage of dying cells when exposed to PTX (40-60%), the percentage was sensibly reduced (20-30%) in favor of living cells if T 3 was present. Cell cycle analysis showed that cells exposed to PTX alone were first collected in G2 and then died by apoptosis; on the other hand, the T 3 granted the cells to cycle regularly and survive PTX insult. In addition, western blot and FCM analyses confirmed that caspases activation, casp 3 and Bax, were downregulated by T 3 and that Bcl2 and cyclins A and B together with cdk1 were upregulated by T 3 . In conclusion, we demonstrated that thyroid hormone T 3 can counteract the lethal effect of taxol on granulosa cells.

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Section: Discussionmentioning

confidence: 99%

T3 preserves ovarian granulosa cells from chemotherapy-induced apoptosis

Falzacappa¹,

Timperi²,

Bucci³

et al. 2012

Journal of Endocrinology

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“…Retroviral transduction has been used to upregulate MDR1 in a granulosa cell line in order to reduce the uptake of chemotherapeutic agents into these cells. This upregulation of MDR1 was reported to protect granulosa cells from the toxic effects of both DOX and paclitaxel in a dose-dependent manner, with the MDR1-transduced granulosa cells showing significantly increased cell survival following treatment with either drug (Salih, 2011). These results are supported by other studies, where the inhibition of MDR transporters in human and mouse oocytes, as well as deletion of the gene in mice, has led to increased susceptibility to CPM toxicity (Brayboy et al., 2017; Wang et al., 2018; Brayboy et al., 2013).…”

Section: Ovarian Damage From Chemotherapy and Its Potential Protectionmentioning

confidence: 99%

Ovarian damage from chemotherapy and current approaches to its protection

Spears

Lopes

Stefansdottir

et al. 2019

Human Reproduction Update

388

263

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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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“…Transduction of the multidrug resistance gene ( MDR1 ) into follicles can help them avoid chemotherapy-induced damage. The KK15 cell line is an immortalized murine granulosa cell line that after transduction can express high levels of biologically active MDR1 and has shown greater tolerance to doxorubicin and paclitaxel treatment and higher cell viability [150]. Nevertheless, MDR1 is also a way by which tumor cells escape from chemotherapy, so the safety of using MDR1 transduction in follicles during cancer treatment must be ensured.…”

Section: Potential Protective Treatments To Reduce/recover Chemothmentioning

confidence: 99%

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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Retrovirus-mediated multidrug resistance gene (MDR1) overexpression inhibits chemotherapy-induced toxicity of granulosa cells

Cited by 9 publications

References 40 publications

T3 preserves ovarian granulosa cells from chemotherapy-induced apoptosis

T3 preserves ovarian granulosa cells from chemotherapy-induced apoptosis

Ovarian damage from chemotherapy and current approaches to its protection

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

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