Frontiers in Pharmacology (Aug 2016)

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

  • Liang Wang,
  • Judy Yuet-Wa Chan,
  • Xinhua Zhou,
  • Guozhen Cui,
  • Zhixiang Yan,
  • Li Wang,
  • Ru Yan,
  • Lijun Di,
  • Yuqiang Wang,
  • Maggie Pui-Man Hoi,
  • Luchen Shan,
  • Simon M Y Lee

DOI
https://doi.org/10.3389/fphar.2016.00249
Journal volume & issue
Vol. 7

Abstract

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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.

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