Abstract
We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays anti-tumor 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 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 confer 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.
Highlights
Doxorubicin, an antibiotic classified as belonging to the anthracycline group, is one of the most effective broad-spectrum anti-cancer drugs and is extensively used for the treatment of many types of cancers including breast cancer, prostate cancer, and ovarian cancer
Dox treatment alone induced apoptosis in MCF-7 cells, and the combination of DT-010 and Dox further increased cell apoptosis (Figures 2B,C). This is consistent with the data showing that the expression of apoptosis-related proteins p53 and cleaved-PARP increased after Dox treatment (Figures 2D–F), which was further amplified after DT-010 and Dox co-treatment
To determine whether there were synergistic anti-tumor effects of DT-010 in combination with Dox via the inhibition of GRP78 expression, MCF-7 cells were co-treated with DT-010 and the endoplasmic reticulum (ER) stress suppressor, 4-PBA
Summary
Doxorubicin, an antibiotic classified as belonging to the anthracycline group, is one of the most effective broad-spectrum anti-cancer drugs and is extensively used for the treatment of many types of cancers including breast cancer, prostate cancer, and ovarian cancer. To minimize its toxicity in heart, and multidrug resistant response in cancer cells, many strategies – such as combination with other anti-cancer or cardioprotective drugs – have been tried (Das et al, 2010; Demetri et al, 2012). ATF4 (activating transcription factor 4), an ER stress response factor, was demonstrated as a transcriptional regulator of glycolysis (Lee et al, 2015). GRP78, a regulator of ER stress, is associated with aerobic glycolysis in cancer cells (Li et al, 2015). Many kinds of cancer cells exhibit increased expression of GRP78 protein in the tumor microenvironment, resulting in tumor survival, metastasis and resistance to chemotherapy (Lee, 2007). Inhibition of GRP78 is a strategy to overcome chemotherapeutic resistance and improve cancer therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
