Novel sesquiterpene lactone analogues as potent anti-breast cancer agents

Kyoko Nakagawa-Goto, Jo Yu Chen, Yu Ting Cheng, Wai Leng Lee, Munehisa Takeya, Yohei Saito, Kuo Hsiung Lee, Lie Fen Shyur

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    18 Citations (Scopus)

    Abstract

    Triple-negative breast cancer (TNBC) is associated with high grade, metastatic phenotype, younger patient age, and poor prognosis. The discovery of an effective anti-TNBC agent has been a challenge in oncology. In this study, fifty-eight ester derivatives (DETDs) with a novel sesquiterpene dilactone skeleton were organically synthesized from a bioactive natural product deoxyelephantopin (DET). Among them, DETD-35 showed potent antiproliferative activities against a panel of breast cancer cell lines including TNBC cell line MDA-MB-231, without inhibiting normal mammary cells M10. DETD-35 exhibited a better effect than parental DET on inhibiting migration, invasion, and motility of MDA-MB-231 cells in a concentration-dependent manner. Comparative study of DETD-35, DET and chemotherapeutic drug paclitaxel (PTX) showed that PTX mainly caused a typical time-dependent G2/M cell-cycle arrest, while DETD-35 or DET treatment induced cell apoptosis. In vivo efficacy of DETD-35 was evaluated using a lung metastatic MDA-MB-231 xenograft mouse model. DETD-35 significantly suppressed metastatic pulmonary foci information along with the expression level of VEGF and COX-2 in SCID mice. DETD-35 also showed a synergistic antitumor effect with PTX in vitro and in vivo. This study suggests that the novel compound DETD-35 may have a potential to be further developed into a therapeutic or adjuvant agent for chemotherapy against metastatic TNBC.

    Original languageEnglish
    Pages (from-to)921-937
    Number of pages17
    JournalMolecular Oncology
    Volume10
    Issue number6
    DOIs
    Publication statusPublished - Jun 2016

    Keywords

    • Deoxyelephantopin
    • DET derivatives
    • Lung metastasis
    • Paclitaxel
    • Triple-negative breast cancer

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