Fluoxetine-Conjugated Platinum(IV) Prodrugs Targeting eEF2K and Conquering Multidrug Resistance against
Jia-Qian Wang1, Xiao-Meng Liu1, Zi-Shuo Zhu1
1Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Abstract:
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.
Insights
Novel dual-action prodrugs targeting eukaryotic elongation factor-2 kinase (eEF2K) show significant promise for treating triple-negative breast cancer (TNBC). These agents enhance chemotherapy efficacy and reduce toxicity in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with poor prognosis.
- Eukaryotic elongation factor-2 kinase (eEF2K) overexpression correlates with TNBC malignancy and is a potential therapeutic target.
- Developing novel therapeutic strategies to overcome TNBC chemoresistance and improve treatment outcomes is crucial.
Purpose of the Study:
- To synthesize and evaluate novel two-in-one prodrugs combining an eEF2K inhibitor (Fluoxetine) with platinum-based chemotherapeutics (cisplatin/oxaliplatin).
- To assess the efficacy of these prodrugs against TNBC cell lines, including chemoresistant models.
- To investigate the in vivo therapeutic potential, toxicity profile, and immunomodulatory effects of the developed prodrugs.
Main Methods:
- Synthesis of Fluoxetine-conjugated cisplatin/oxaliplatin prodrugs (compounds 8-19).
- In vitro cytotoxicity assays against MDA-MB-231 and A549cisR cells.
- Western blot analysis to assess chemoresistance-related proteins (P-gp, GST-π, ATM, RAD51).
- In vivo studies using syngeneic and xenograft mouse models to evaluate tumor growth, metastasis, and toxicity.
- Immunomodulatory assays measuring T-cell proliferation and Th1 cytokine production.
Main Results:
- Prodrugs 8 and 12 demonstrated significantly higher cytotoxicity than cisplatin against TNBC cells, inducing apoptosis and autophagy.
- Compounds 8 and 12 effectively overcame chemoresistance in A549cisR cells by downregulating key resistance proteins.
- In vivo studies showed that prodrugs 8 and 12 inhibited tumor growth and metastasis while exhibiting reduced toxicity compared to cisplatin.
- Prodrugs 8 and 12 stimulated immunomodulatory responses, including enhanced T-cell proliferation and Th1 cytokine production.
Conclusions:
- Novel prodrugs 8 and 12, combining eEF2K inhibition with platinum chemotherapy, are effective multifunctional agents against TNBC.
- These prodrugs show potential for overcoming chemoresistance, reducing toxicity, and modulating the immune response.
- Compounds 8 and 12 represent promising candidates for advanced TNBC chemotherapeutic development.
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