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 8–19. Multievaluation
indicated that monosubstituted 8 and disubstituted 12 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, 8 and 12 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 8 and 12 could effectively
inhibit tumor growth and metastasis, and reduce toxicity compared
to cisplatin in vivo. Additionally, 8 and 12 stimulated immunomodulation including T-cell
proliferation and Th1 cytokine production. All results hold the promise
of 8 and 12 as multifunctional chemotherapeutic
agents.