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  • 1
    Online Resource
    Online Resource
    Sepiolite Clay Attenuates the Development of Hypercholesterolemia and Obesity in Mice Fed a High-Fat High-Cholesterol Diet
    Mary Ann Liebert Inc ; 2020
    In:  Journal of Medicinal Food Vol. 23, No. 3 ( 2020-03-01), p. 289-296
    Details
    In: Journal of Medicinal Food, Mary Ann Liebert Inc, Vol. 23, No. 3 ( 2020-03-01), p. 289-296
    Type of Medium: Online Resource
    ISSN: 1096-620X , 1557-7600
    URL: Article
    DOI: 10.1089/jmf.2019.0030
    Language: English
    Publisher: Mary Ann Liebert Inc
    Publication Date: 2020
    detail.hit.zdb_id: 2030886-3
    SSG: 15,3
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  • 2
    Online Resource
    Online Resource
    2-Hydroxyestradiol Overcomes Mesenchymal Stem Cells-Mediated Platinum Chemoresistance in Ovarian Cancer Cells in an ERK-Independent Fashion
    MDPI AG ; 2022
    In:  Molecules Vol. 27, No. 3 ( 2022-01-26), p. 804-
    Details
    In: Molecules, MDPI AG, Vol. 27, No. 3 ( 2022-01-26), p. 804-
    Abstract: Ovarian cancer (OC) is the second most common type of gynecological malignancy. Platinum (Pt)-based chemotherapy is the standard of care for OC, but toxicity and acquired chemoresistance has proven challenging. Recently, we reported that sensitivity to platinum was significantly reduced in a co-culture of OC cells with MSC. To discover compounds capable of restoring platinum sensitivity, we screened a number of candidates and monitored ability to induce PARP cleavage. Moreover, we monitored platinum uptake and expression of ABC transporters in OC cells. Our results showed that 2-hydroxyestradiol (2HE2), a metabolite of estradiol, and dasatinib, an Abl/Src kinase inhibitor, were significantly effective in overcoming MSC-mediated platinum drug resistance. Dasatinib activity was dependent on ERK1/2 activation, whereas 2HE2 was independent of the activation of ERK1/2. MSC-mediated platinum drug resistance was accompanied by reduced intracellular platinum concentrations in OC cells. Moreover, MSC co-cultured with OC cells resulted in downregulation of the expression of cellular transporters required for platinum uptake and efflux. Exposure to 2HE2 and other modulators resulted in an increase in intracellular platinum concentrations. Thus, 2HE2 and dasatinib might act as sensitizers to restore platinum drug sensitivity to OC cells and thus to limit TME-mediated chemoresistance in OC.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules27030804
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2008644-1
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  • 3
    Online Resource
    Online Resource
    Secreted Soluble Factors from Tumor-Activated Mesenchymal Stromal Cells Confer Platinum Chemoresistance to Ovarian Cancer Cells
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 9 ( 2023-04-23), p. 7730-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 9 ( 2023-04-23), p. 7730-
    Abstract: Ovarian cancer (OC) ranks as the second most common type of gynecological malignancy, has poor survival rates, and is frequently diagnosed at an advanced stage. Platinum-based chemotherapy, such as carboplatin, represents the standard-of-care for OC. However, toxicity and acquired resistance to therapy have proven challenging for the treatment of patients. Chemoresistance, a principal obstacle to durable response in OC patients, is attributed to alterations within the cancer cells, and it can also be mediated by the tumor microenvironment (TME). In this study, we report that conditioned medium (CM) derived from murine and human stromal cells, MS-5 and HS-5, respectively, and tumor-activated HS-5, was active in conferring platinum chemoresistance to OC cells. Moreover, CM derived from differentiated murine pre-adipocyte (3T3-L1), but not undifferentiated pre-adipocyte cells, confers platinum chemoresistance to OC cells. Interestingly, CM derived from tumor-activated HS-5 was more effective in conferring chemoresistance than was CM derived from HS-5 cells. Various OC cells exhibit variable sensitivity to CM activity. Exploring CM content revealed the enrichment of a number of soluble factors in the tumor-activated HS-5, such as soluble uPAR (SuPAR), IL-6, and hepatocyte growth factor (HGF). FDA-approved JAK inhibitors were mildly effective in restoring platinum sensitivity in two of the three OC cell lines in the presence of CM. Moreover, Crizotinib, an ALK and c-MET inhibitor, in combination with platinum, blocked HGF’s ability to promote platinum resistance and to restore platinum sensitivity to OC cells. Finally, exposure to 2-hydroxyestardiol (2HE2) was effective in restoring platinum sensitivity to OC cells exposed to CM. Our results showed the significance of soluble factors found in TME in promoting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity to OC cells.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24097730
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Flavonoids Restore Platinum Drug Sensitivity to Ovarian Carcinoma Cells in a Phospho-ERK1/2-Dependent Fashion
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 18 ( 2020-09-07), p. 6533-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 18 ( 2020-09-07), p. 6533-
    Abstract: Ovarian cancer (OC) is the second most common type of gynecological malignancy; it has poor survival rates and is frequently ( 〉 75%) diagnosed at an advanced stage. Platinum-based chemotherapy, with, e.g., carboplatin, is the standard of care for OC, but toxicity and acquired resistance to therapy have proven challenging. Despite advances in OC diagnosis and treatment, approximately 85% of patients will experience relapse, mainly due to chemoresistance. The latter is attributed to alterations in the cancer cells and is also mediated by tumor microenvironment (TME). Recently, we reported the synthesis of a platinum (IV) prodrug that exhibits equal potency toward platinum-sensitive and resistant OC cell lines. Here, we investigated the effect of TME on platinum sensitivity. Co-culture of OC cells with murine or human mesenchymal stem cells (MS-5 and HS-5, respectively) rendered them resistant to chemotherapeutic agents, including platinum, paclitaxel and colchicine. Platinum resistance was also conferred by co-culture with differentiated murine adipocyte progenitor cells. Exposure of OC cells to chemotherapeutic agents resulted in activation of phospho-ERK1/2. Co-culture with MS-5, which conferred drug resistance, was accompanied by blockage of phospho-ERK1/2 activation. The flavonoids fisetin and quercetin were active in restoring ERK phosphorylation, as well as sensitivity to platinum compounds. Exposure of OC cells to cobimetinib—a MEK1 inhibitor that also inhibits extracellular signal-regulated kinase (ERK) phosphorylation—which resulted in reduced sensitivity to the platinum compound. This suggests that ERK activity is involved in mediating the function of flavonoids in restoring platinum sensitivity to OC co-cultured with cellular components of the TME. Our data show the potential of combining flavonoids with standard therapy to restore drug sensitivity to OC cells and overcome TME-mediated platinum drug resistance.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21186533
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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