A platinum(IV) prodrug strategy to overcome glutathione-based oxaliplatin resistance

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Oxaliplatin efficacy is limited by severe side effects and therapy resistance, often linked to elevated glutathione (GSH) levels.
• Glutamate-cysteine ligase is the rate-limiting enzyme in GSH biosynthesis, and its inhibition can potentially resensitize tumors to chemotherapy.

Purpose of the Study:

• To synthesize and characterize novel oxaliplatin(IV)-based prodrugs designed to release both oxaliplatin and L-buthionine-S,R-sulfoximine (BSO), a GSH synthesis inhibitor.
• To evaluate the in vitro and in vivo efficacy, tumor selectivity, and toxicity profile of these novel prodrugs compared to oxaliplatin.

Main Methods:

• Synthesis and characterization of two platinum(IV) prodrugs: BSO-OxOAc and BSO-OxMal.
• In vitro assessment of anticancer activity and drug uptake in resistant cancer cell lines (HCT116/OxR).
• In vivo evaluation of platinum accumulation, tumor selectivity, antitumor activity, and organ toxicity in a colorectal cancer mouse model.

Main Results:

• BSO-OxOAc demonstrated prodrug characteristics with reduced in vitro activity but overcame oxaliplatin resistance in HCT116/OxR cells.
• BSO-OxMal exhibited enhanced tumor selectivity and antitumor activity in vivo, leading to improved overall survival compared to oxaliplatin.
• BSO-OxMal treatment reduced tumor GSH levels, proliferative activity, and increased DNA damage (pH2AX), while notably decreasing kidney toxicity observed with oxaliplatin.

Conclusions:

• The developed oxaliplatin(IV)/BSO prodrugs show promise in overcoming oxaliplatin resistance and enhancing tumor specificity.
• BSO-OxMal represents a promising strategy for improving the therapeutic index of oxaliplatin chemotherapy by targeting GSH-mediated resistance and reducing off-target toxicity.