Astragaloside IV Enhances the Effect of Elesclomol on Chemoresistance and Stemness of Colorectal Cancer Cells by Targeting Akt Signaling

ColoRectal Cancer (CRC) is one of the most common malignancies, and the development of chemoresistance severely limits patient prognosis and survival. EleSclomol (ES), a copper chelator, has been reported to induce cuprotosis in cancer cells, while AstragaloSide IV (AS-IV), an active compound extracted from Astragalus membranaceus, exhibits potent anti-cancer effects. We investigated whether AS-IV enhances the anti-tumor efficacy of ES in oxaliplatin-resistant CRC cells. Oxaliplatin-resistant CRC cell lines (SW۴۸۰-DR and SW۶۲۰-DR) were treated with AS-IV, ES, or their combination. Cell proliferation and viability were evaluated using CCK-۸, colony formation, and EdU assays. Tumor growth in vivo was assessed using a xenograft mouse model. Cancer cell stemness was examined via sphere formation assays, and expression of stemness markers and PI۳K/AKT pathway proteins was analyzed by Western blotting. An AKT activator was applied to confirm the involvement of PI۳K/AKT signaling. AS-IV significantly enhanced the inhibitory effect of ES on both in vitro and in vivo growth of oxaliplatin-resistant CRC cells. Combination treatment suppressed the sphere-forming ability and reduced the expression of stemness markers (CD۱۳۳, CD۴۴, Sox۹, and Nanog). Furthermore, the combination inactivated PI۳K/AKT signaling, while AKT activation partially reversed the observed anti-proliferative effects. These findings suggest that AS-IV synergistically enhances the anti-tumor activity of ES and reduces stemness in oxaliplatin-resistant CRC cells by inhibiting PI۳K/AKT signaling, providing a potential therapeutic strategy to overcome chemoresistance in CRC.

کلیدواژه ها:

Colorectal cancer ، Chemoresistance ، Astragaloside IV ، Akt ، Stemness