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    A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin

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    Author
    Zhang, Ruijie
    Yang, Xiaozhi
    Roque, Dana M
    Li, Chenglong
    Lin, Jiayuh
    Date
    2021-04-28
    Journal
    PLoS ONE
    Publisher
    Public Library of Science
    Type
    Article
    
    Metadata
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    See at
    https://doi.org/10.1371/journal.pone.0240145
    Abstract
    Ovarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin-paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cells and suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.
    Keyword
    chemoresistance
    LLL12B
    Ovarian Neoplasms--drug therapy
    STAT3 Transcription Factor--antagonists & Inhibitors
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/15599
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0240145
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