A novel agent enhances the chemotherapeutic efficacy of doxorubicin in MCF-7 breast cancer cells

• मुख्य लेखकों: Liang Wang (लेखक), Judy Yuet-Wa Chan (लेखक), Xinhua Zhou (लेखक), Guozhen Cui (लेखक), Zhixiang Yan (लेखक), Li Wang (लेखक), Ru Yan (लेखक), Lijun Di (लेखक), Yuqiang Wang (लेखक), Maggie Pui-Man Hoi (लेखक), Luchen Shan (लेखक), Simon M Y Lee (लेखक)
• स्वरूप: पुस्तक
• प्रकाशित: Frontiers Media S.A., 2016-08-01T00:00:00Z.
• विषय: article
• ऑनलाइन पहुंच: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2016.00249
• Keywords: Doxorubicin; Glycolysis; breast cancer; Tetramethylpyrazine; Danshensu; GRP78 protein; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 7 (2016)

We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays antitumor effects in breast cancer cells both in vitro and in vivo. In the present study, we investigated whether DT-010 enhances the chemotherapeutic effect of doxorubicin (Dox) in MCF-7 breast cancer cells and exerts concurrent cardioprotective benefit at the same time. Our findings showed that DT-010 was more potent than TMP, DSS or their combination in potentiating Dox-induced toxicity in MCF-7 cells. Co-treatment with DT-010 and Dox increased apoptosis in MCF-7 cells relative to Dox alone. Further study indicated that glycolytic capacity, glycolytic reserve and lactate level of MCF-7 cells were significantly inhibited after DT-010 treatment. DT-010 also increased the expression of the pro-survival protein GRP78, which was inhibited by co-treatment with Dox. Both endoplasmic reticulum (ER) stress inhibitor 4-PBA and knockdown of the expression of GRP78 protein potentiated DT-010-mediated apoptosis in MCF-7 cells. Moreover, DT-010 inhibited Dox-induced cardiotoxicity in H9c2 myoblasts. In conclusion, DT-010 and Dox confers synergistic anti-tumor effect in MCF-7 breast cancer cells through downregulation of the glycolytic pathway and inhibition of the expression of GRP78. Meanwhile, DT-010 also protects against Dox-induced cardiotoxicity.