Piperlongumine Induces Apoptosis and Synergizes with Doxorubicin by Inhibiting the JAK2-STAT3 Pathway in Triple-Negative Breast Cancer

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-06, Vol.24 (12), p.2338
• Main Authors: Chen, Di, Ma, Yangmin, Li, Peiqi, Liu, Meng, Fang, Yuan, Zhang, Jiejie, Zhang, Bilin, Hui, Yuyu, Yin, Yue
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Apoptosis; Apoptosis - drug effects; BAX protein; Bcl-2 protein; Breast cancer; Cancer therapies; Caspase-3; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Cytotoxicity; Dioxolanes - pharmacology; Disease Models, Animal; Doxorubicin; Doxorubicin - pharmacology; Drug dosages; Drug resistance; Drug Synergism; Drugs; Epidermal growth factor; Female; Flow cytometry; Glutathione transferase; Growth factors; GTP-binding protein; Humans; JAK2; Janus kinase 2; Janus Kinase 2 - metabolism; MAP kinase; Medical prognosis; Mice; NF-κB protein; piperlongumine; Poly(ADP-ribose) polymerase; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Side effects; Signal Transduction - drug effects; STAT3; Stat3 protein; STAT3 Transcription Factor - metabolism; TOR protein; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; triple-negative breast cancer; Xenograft Model Antitumor Assays
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24122338

Triple-negative breast cancer (TNBC) lacks major effective target molecules and chemotherapy remains the current main treatment. However, traditional chemotherapy drugs, such as doxorubicin (DOX), cause serious side effects and have a poor prognosis. Piperlongumine (PL), a natural alkaloid, has showed selective anticancer effects and is expected to become a new strategy against TNBC. In our research, cell viability, colony formation, flow cytometry, Western blot, and tumor xenograft model assays were established to evaluate the suppression effect of PL and DOX alone and in combination. Data showed that PL could effectively inhibit cell growth and induce apoptosis in two TNBC cell lines. We also demonstrated for the first time that the combination treatment of PL and DOX synergistically inhibited cell growth and induced apoptosis in TNBC cells. The suppression of STAT3 activation was indicated to be a mechanism of the anticancer effect. Moreover, the effectiveness of this combination was confirmed in a tumor xenograft model. These results revealed that inhibition of the JAK2-STAT3 pathway was a key anticancer mechanism when treated with PL alone or combined with DOX, suggesting that the combination of PL and chemotherapy drugs may be a potential strategy for the clinical treatment of TNBC.