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Signal transducer and activator of transcription 3 (STAT3) is a well-known antitumor target. Exogenous ROS insult can lead to selective cytotoxicity against cancer cells. A combination of STAT3 inhibition and “oxidation therapy” may be a new strategy to address the multidrug-resistance issue due to their important roles in the survival and drug resistance of cancer cells. Here, a series of novel curcumin-BTP hybrids were designed and evaluated as STAT3 inhibitors with ROS production activity. Compound  6b  exerted the best antitumor activity and selectivity for MCF-7 and MCF-7/DOX cells (IC 50  = 0.52 μM and 0.40 μM, respectively), while its IC 50  value for MCF-10A breast epithelial cells was 7.72 μM. Furthermore, compound  6b  suppressed STAT3 phosphorylation, nuclear translocation and DNA-binding activity and the expression of STAT3 specific oncogenes. Increases in the level of IL-6-induced p-STAT3 were also inhibited by  6b  without influencing IFN-γ-induced p-STAT1 expression. Additionally,  6b  effectively promoted intracellular ROS accumulation, induced cancer cell apoptosis and cell cycle arrest, abolished the colony formation ability of breast cancer cells, and inhibited P-gp expression in MCF-7/DOX cells. Finally,  6b  suppressed the growth of implanted human breast cancer  in vivo . Our findings highlight that  6b  may be a promising therapeutic agent for drug-sensitive and drug-resistant breast cancers.

Discovery of monocarbonyl curcumin-BTP hybrids as STAT3 inhibitors for drug-sensitive and drug-resistant breast cancer therapy