A peptide-salinomycin conjugate with a bystander effect reduces the stemness characteristics of ovarian cancer cells and enhances drug sensitivity

• Published in: European journal of medicinal chemistry 2024-10, Vol.276, p.116701, Article 116701
• Main Authors: Hao, Chaowei, Chen, Peng, Setrerrahmane, Sarra, Xu, Hanmei
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bystander Effect - drug effects; Bystander killing effect; Cancer stem cell; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Female; Humans; Molecular Structure; Neoplastic Stem Cells - drug effects; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Peptide drug conjugates; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Polyether Polyketides; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - pharmacology; Salinomycin; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116701

Salinomycin (Sal) has attracted considerable attention in the field of tumor treatment, especially for its inhibitory effect on cancer stem cells (CSCs) and drug-resistant tumor cells. However, its solubility and targeting specificity pose significant challenges to its pharmaceutical development. Sal-A6, a novel peptide-drug conjugate (PDC), was formed by linking the peptide A6 targeting the CSC marker CD44 with Sal using a specific linker. This conjugation markedly enhances the physicochemical properties of Sal and compared to Sal, Sal-A6 demonstrated a significantly increased activity against ovarian cancer. Furthermore, Sal-A6, employing a disulfide bond as a linker, exhibited bystander killing effect. Moreover, it induces substantial cytotoxic effect on both cancer stem cells and drug-resistant cells in addition to enhance chemosensitivity of resistant ovarian cancer cells. In summary, the results indicated that Sal-A6, a novel PDC derived from Sal, has potential therapeutic applications in the treatment of ovarian cancer and drug-resistant patients. Additionally, this discovery offers insights for developing PDC-type drugs using Sal as a foundation. [Display omitted] •Novel Sal-A6 conjugate with a significant solubility improvement.•Sal-A6 specifically targets CD44 with a threefold increase in cell toxicity.•Sal-A6 demonstrated bystander killing effects.•Sal-A6 demonstrates a substantial inhibitory effect on CSCs surpassing Sal activity.•Significant cytotoxicity against drug-resistant tumor cells with drug-sensitizing effects.