Fluoxetine-Conjugated Platinum(IV) Prodrugs Targeting eEF2K and Conquering Multidrug Resistance against Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) poses formidable challenges in the clinic owing to its particularly malignant and aggressive properties. Overexpression of eukaryotic elongation factor-2 kinase (eEF2K) is highly correlated with the poor prognosis of TNBC, representing a promising therapeutic target. Herein, Fluoxetine as eEF2K-inhibitor and chemosensitizer was conjugated with cisplatin/oxaliplatin to present two-in-one prodrugs <b>8</b>-<b>19</b>. Multievaluation indicated that monosubstituted <b>8</b> and disubstituted <b>12</b> exhibited 407- and 174-fold higher cytotoxicity than cisplatin against MDA-MB-231 cells by elevating DNA damage-induced apoptosis and eEF2K-triggered autophagy. Moreover, <b>8</b> and <b>12</b> significantly overcame chemoresistance in A549cisR cells, evidenced by downregulating resistance-related key proteins P-gp, GST-π, ATM, and RAD51. Syngeneic and xenograft mouse models demonstrated that <b>8</b> and <b>12</b> could effectively inhibit tumor growth and metastasis, and reduce toxicity compared to cisplatin <i>in vivo</i>. Additionally, <b>8</b> and <b>12</b> stimulated immunomodulation including T-cell proliferation and Th1 cytokine production. All results hold the promise of <b>8</b> and <b>12</b> as multifunctional chemotherapeutic agents.