An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation

Abstract

Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with shorter five-year survival than other breast cancer subtypes, and lacks targeted and hormonal treatment strategies. The signal transducer and activator of transcription 3 (STAT3) signaling is up-regulated in various tumors, including TNBC, and plays a vital role in regulating the expression of multiple proliferation- and apoptosis-related genes. Results: By combining the unique structures of the natural compounds STA-21 and Aulosirazole with antitumor activities, we synthesized a class of novel isoxazoloquinone derivatives and showed that one of these compounds, ZSW, binds to the SH2 domain of STAT3, leading to decreased STAT3 expression and activation in TNBC cells. Furthermore, ZSW promotes STAT3 ubiquitination, inhibits the proliferation of TNBC cells in vitro, and attenuates tumor growth with manageable toxicities in vivo. ZSW also decreases the mammosphere formation of breast cancer stem cells (BCSCs) by inhibiting STAT3. Conclusions: We conclude that the novel isoxazoloquinone ZSW may be developed as a cancer therapeutic because it targets STAT3, thereby inhibiting the stemness of cancer cells.

Naphthoquinone Derivative ZSW-4B Induces Apoptosis in Triple-negative Breast Cancer via AMPK signal Activation

“…In previous studies, we synthesized a series of 1, 4-naphthoquinone compounds, including ZSW-4B (Figure 1A). We found that ZSW-4B demonstrates potent antitumor effect and enhanced selective toxicity 12 . To con rm which subtypes of breast cancer cells ZSW-4B tends to inhibit proliferation, we treated two immortalized normal breast cancer cell lines (MCF10A, 184B5), one luminal subtype cell line (MCF-7), and four TNBC cell line (MDA-MB-231, HCC1937, Hs875T, BT549).…”

“…Based on the chemical structures, the can function as proteasome inhibitors 32 , hNAT1 inhibitors 33 , Cdc25 phosphatase inhibitors 34 , topoisomerase II inhibitors 35 , Hsp90 inhibitors 36 , indoleamine-2,3-dioxygenase 1(IOD1) inhibitors 37 and NQO1 inhibitors 33 . In our previous research, we synthesized the isoxzoloquinone derivative ZSW, and found that it exerts anti-tumor effect by triggering the ubiquitin-dependent degradation of STAT3, suppressing the TNBC stem cell like properties 12 . Here, we reported ZSW-4B as the rst naphthoquinone derivative capable of activating AMPK.…”

“…These compounds have been reported to exhibit diverse biological activities, such as anti-tumor, anti-bacterial, anti-fungal and anti-in ammatory properties 11 . In previous research, we synthesized and screened a class of naphthoquinone compounds, including ZSW and ZSW-4B, and found that ZSW inhibits TNBC stem cells by modulating the ubiquitination of STAT3 12 . Here we demonstrated that another 1, 4-naphthoquinone compound, ZSW-4B, exhibits favorable antitumor effect and improved selective cytotoxicity against TNBC cells.…”

Potential therapeutic targets of the JAK2/STAT3 signaling pathway in triple-negative breast cancer

“…In vitro studies have demonstrated Napabucasin’s capability to reduce TNBC cell viability ( 156 ). Additionally, a series of compounds, such as 7a ( 157 ), SLSI-1216 ( 158 ), H182 ( 159 ), SMY002 ( 160 ), MC0704 ( 161 ), ZSW ( 162 ), and Acetyl-cinobufagin ( 163 ), have been identified to selectively inhibit STAT3 phosphorylation by binding to its SH2 domain and suppressing TNBC cell viability in vitro . Arctigenin, a bioactive lignan isolated from the seeds of Arctium lappa, inhibits STAT3 in TNBC cells by binding to its SH2 domain, thereby disrupting hydrogen bond connections between DNA and STAT3.…”