Cordycepin-double staple peptide-paclitaxel conjugate enhanced antitumor activity via autophagy and apoptosis pathways.

Cancer is one of the major diseases threatening human health worldwide. The numerous side effects exhibited by the traditional anti-cancer drugs can significantly limit their curative effects. In recent years, it has been found that the combination of drugs can greatly reduce the dosage of drugs, which will play a complementary role and can also enhance the anti-cancer efficacies. In this study, we advanced the structural modification of 3'-dA, yielding StLK-24, a bis-stapled peptide variant exhibiting augmented stability. Subsequent reaction with Paclitaxel (PTX) culminated in the formation of the tripartite compound 3'-dA-StLK-24-PTX, which demonstrated greater antineoplastic activity than its binary counterpart. This compound induced autophagic responses in tumor cells and promoted Ca2+ efflux from the endoplasmic reticulum into the cytosol, facilitating the calpain-mediated conversion of ATG5 from a full-length protein to its truncated form, tATG5-N, and elevating tBeclin-1C. tATG5-N and tBeclin-1C synergistically induced tumor cell apoptosis through mitochondrial pathways. These findings underscored the improved stability and potentiated antitumor efficacy of 3'-dA-StLK-24-PTX, reflecting the principle that the combined efficacy of the compound constituents exceeds their isolated actions. In conclusion, this investigation provides foundational insights for novel antitumor drug screening and offers a new dimension to cancer therapeutic strategy.