Deciphering the Comprehensive Structure–Activity Relationship of Sunshinamide for Breast Cancer Therapy through Dual Modulation of Apoptotic and Ferroptotic Pathways via TrxR1 and Gpx4 Inhibition

Sunshinamide, a cyclodepsipeptide, has demonstrated significant
potential in inhibiting cancer cell proliferation. Our prior research
established the total synthesis and anticancer properties of sunshinamide.
However, a deeper understanding of the structure–activity relationship
(SAR) of sunshinamide remained imperative. In this study, we aimed
to elucidate the SAR and mechanistic insights underlying sunshinamide
action, both in vitro and in vivo. SAR studies confirm the crucial
roles of both the bicyclic-ring and disulfide moiety in the anticancer
activity of sunshinamide. Our recent findings unveil that sunshinamide
targets TrxR1, leading to ROS generation and ER-stress-mediated apoptosis,
while also promoting lipid peroxidation by targeting Gpx4, rendering
cancer cells vulnerable to ferroptosis. In vivo, experiments demonstrated
the effectiveness of sunshinamide in reducing tumor growth by inducing
both apoptosis and ferroptosis. The dual efficacy of sunshinamide
in eliciting apoptosis and ferroptosis positions it as a promising
candidate for breast cancer therapy, addressing the challenge of chemoresistance.