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Gamma Tocopherol Reduced Chemotherapeutic-Induced ROS in an Ovarian Granulosa Cell Line, But Not in Breast Cancer Cell Lines In Vitro.

ABSTRACT: Doxorubicin and cyclophosphamide are used to treat breast cancer, but they also cause infertility through off-target cytotoxicity towards proliferating granulosa cells that surround eggs. Each chemotherapeutic generates reactive oxygen species (ROS) but the effects of the combination, or the antioxidants alpha (?Toc) and gamma tocopherol (?Toc) on ROS in breast cancer or ovarian cells are unknown. Human breast cancer (MCF7, T47D) and ovarian cancer (OVCAR, COV434) cells were loaded with DCDFA and exposed (1, 2, 3, 24 h) to the MCF7-derived EC25 values of individual agents, or to combinations of these. ROS were quantified and viable cells enumerated using crystal violet or DAPI. Each chemotherapeutic killed ~25% of MCF7, T47D and OVCAR cells, but 57 ± 2% (doxorubicin) and 66 ± 2% (cyclophosphamide) of the COV434 granulosa cells. The combined chemotherapeutics decreased COV434 cell viability to 34 ± 5% of control whereas doxorubicin + cyclophosphamide + ?Toc reduced ROS within 3 h (p < 0.01) and reduced cytotoxicity to 54 ± 4% (p < 0.05). ?Toc was not cytotoxic, whereas ?Toc killed ~25% of the breast cancer but none of the ovarian cells. Adding ?Toc to the combined chemotherapeutics did not change ROS or cytotoxicity in MCF7, T47D or OVCAR cells. The protection ?Toc afforded COV434 granulosa cells against chemotherapy-induced ROS and cytotoxicity suggests potential for fertility preservation.

SUBMITTER: Figueroa Gonzalez D

PROVIDER: S-EPMC7023168 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Gamma Tocopherol Reduced Chemotherapeutic-Induced ROS in an Ovarian Granulosa Cell Line, But Not in Breast Cancer Cell Lines In Vitro.

Figueroa Gonzalez Daniela D Young Fiona F

Antioxidants (Basel, Switzerland) 20200107 1

Doxorubicin and cyclophosphamide are used to treat breast cancer, but they also cause infertility through off-target cytotoxicity towards proliferating granulosa cells that surround eggs. Each chemotherapeutic generates reactive oxygen species (ROS) but the effects of the combination, or the antioxidants alpha (αToc) and gamma tocopherol (γToc) on ROS in breast cancer or ovarian cells are unknown. Human breast cancer (MCF7, T47D) and ovarian cancer (OVCAR, COV434) cells were loaded with DCDFA an ...[more]

PMID: 31936058

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Project description:The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation.

Dataset Information

Gamma Tocopherol Reduced Chemotherapeutic-Induced ROS in an Ovarian Granulosa Cell Line, But Not in Breast Cancer Cell Lines In Vitro.

Publications

Gamma Tocopherol Reduced Chemotherapeutic-Induced ROS in an Ovarian Granulosa Cell Line, But Not in Breast Cancer Cell Lines In Vitro.

Similar Datasets

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