RETRACTED ARTICLE: A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy

Abstract

Silencing STAT3 is confirmed as a promising therapeutic strategy for triple-negative breast cancer (TNBC) therapy to address the issue of its poor prognosis. In this study, the natural product cryptotanshinone was firstly remodeled and modified as a more effective STAT3 inhibitor by structure-based strategy. The synthetic derivative KYZ3 had 22–24-fold increase in antitumor activity than cryptotanshinone on two TNBC cell lines but had little effect on normal breast epithelial MCF-10A cells. Further investigation showed that KYZ3 inhibited persistent STAT3 phosphorylation. It also prevented the STAT3 protein nuclear translocation to regulate the expressions of the target oncogenes including Bax and Bcl-2. Furthermore, KYZ3 inhibited TNBC cell metastasis by decreasing the levels of MMP-9 which were directly regulated by activated STAT3. A STAT3 plasmid transfecting assay suggested that KYZ3 induced tumor cell apoptosis mainly by targeting STAT3. Finally, KYZ3 suppressed the growth of tumors resulting from subcutaneous implantation of MDA-MB-231 cells in vivo. Taken together, KYZ3 may be a promising cancer therapeutic agent for TNBC.

Cryptotanshinone Inhibites Bladder Cancer Cell Proliferation and Promotes Apoptosis via the PTEN/PI3K/AKT Pathway

“…Moreover, in tumourbearing mice, we showed a high propensity of CTT to inhibit proliferation and metastasis of bladder cells without apparent toxicity-related events or significant body weight changes. CTT, a natural active element extracted from Salvia miltiorrhiza Bunge (Danshen), has antitumour activity towards a broad spectrum of cancer types, including breast cancer, liver cancer and malignancies of the alimentary tract, and it is associated with a low level of toxicity and is well tolerated by patients with cancer [25][26][27][28]. Consistent with other reports, this study showed that CTT exhibited high levels of anticancer activity on 5637 and T24 bladder cancer cells by suppressing survival and promoting apoptosis [29].…”

Role of STAT3 signaling pathway in breast cancer

“…Sravanthi et al have screened 29,388 ligands docking with STAT3 and found that Risedronate Sodium (RES) and Zoledronic acid (ZOL) could tightly combine with STAT3 and show significant cytotoxicity in breast cancer cells [105]. Moreover, a new synthetic derivative of cryptotanshinone KYZ3 is found to directly bind to the SH2 domain of STAT3 and act as a new STAT3 inhibitor [101]. Napabucasin and its angularly anellated isomer could also combine with SH2 domain of STAT3 [102].…”

STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review

“…Cryptotanshinone is a well-documented natural product inhibitor of STAT3, which also binds to the SH2 domain and inhibits the phosphorylation and dimerization of STAT3 [112]. KYZ3, a synthetic derivative of cryptotanshinone has recently been developed and shown to exert anticancer activity in TNBC cells in vitro and in vivo through binding to and inhibiting STAT3 activation [113]. However, none of these compounds have been evaluated for their binding affinity to STAT3.…”