Although many anticancer drugs have been developed for triple-negative breast cancer (TNBC) treatment, there are no obvious therapies. Moreover, the combination of epidermal growth factor receptor- (EGFR-) targeted therapeutics and classical chemotherapeutic drugs has been assessed in clinical trials for TNBC treatment, but those are not yet approved. Our serial studies for newly developed herbal medicine named SH003 provide evidence of its broad effectiveness in various cancers, especially on TNBC. The current study demonstrates a synergic effect of combinatorial treatment of SH003 and docetaxel (DTX) by targeting EGFR activation. The combinatorial treatment reduced the viability of both BT-20 and MDA-MB-231 TNBC cells, displaying the synergism. The combination of SH003 and DTX also caused the synergistic effect on apoptosis. Mechanistically, the cotreatment of SH003 and DTX inhibited phosphorylation of EGFR and AKT in both BT-20 and MDA-MB-231 cells. Moreover, our xenograft mouse tumor growth assays showed the inhibitory effect of the combinatorial treatment with no effect on body weight. Our immunohistochemistry confirmed its inhibition of EGFR phosphorylation in vivo. Collectively, combinatorial treatment of SH003 and DTX has a synergistic anticancer effect at a relatively low concentration by targeting EGFR in TNBC, indicating safety and efficacy of SH003 as adjuvant combination therapy with docetaxel. Thus, it is worth testing the combinatorial effect in clinics for treating TNBC.
Exosomes released from tumor cells treated with cancer-targeting drugs reflect altered metabolic processes within the cells. Therefore, metabolites in exosomes can be used as markers to predict the therapeutic response or identify therapeutic targets. In this study, metabolite changes in exosomes were investigated by co-administration of the herbal extract SH003 and docetaxel (DTX), which exert a synergistic anti-cancer effect on lung cancer cells. Exosomes released from cells treated with SH003 and DTX were purified, and untargeted metabolic profiling was performed by liquid chromatography–tandem mass spectrometry. Analysis of altered metabolic-based pathways showed that the combined treatment synergistically increased pyrimidine metabolism compared with single-drug treatment. Additionally, xenobiotic metabolism by cytochrome P450 was specifically increased in cells treated with the combination. However, the released exosomes and increased metabolites in exosomes did not affect the anti-cancer effect of SH003 and DTX. Therefore, our study suggests that metabolite profiling can be used to evaluate the efficacy of combined treatments. Furthermore, such exosome-based metabolism may facilitate understanding the physiological endpoints of combination therapy in human biofluids.
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