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A platinum(IV) prodrug strategy to overcome glutathione-based oxaliplatin resistance
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Journal Article
A platinum(IV) prodrug strategy to overcome glutathione-based oxaliplatin resistance
2022
Overview
Clinical efficacy of oxaliplatin is frequently limited by severe adverse effects and therapy resistance. Acquired insensitivity to oxaliplatin is, at least in part, associated with elevated levels of glutathione (GSH). In this study we report on an oxaliplatin-based platinum(IV) prodrug, which releases
L
-buthionine-
S
,
R
-sulfoximine (BSO), an inhibitor of glutamate-cysteine ligase, the rate-limiting enzyme in GSH biosynthesis. Two complexes bearing either acetate (
BSO-OxOAc
) or an albumin-binding maleimide (
BSO-OxMal
) as second axial ligand were synthesized and characterized. The in vitro anticancer activity of
BSO-OxOAc
was massively reduced in comparison to oxaliplatin, proving its prodrug nature. Nevertheless, the markedly lower intracellular oxaliplatin uptake in resistant HCT116/OxR cells was widely overcome by
BSO-OxOAc
resulting in distinctly reduced resistance levels. Platinum accumulation in organs of a colorectal cancer mouse model revealed higher tumor selectivity of
BSO-OxMal
as compared to oxaliplatin. This corresponded with increased antitumor activity, resulting in significantly enhanced overall survival.
BSO-OxMal
-treated tumors exhibited reduced GSH levels, proliferative activity and enhanced DNA damage (pH2AX) compared to oxaliplatin. Conversely, pH2AX staining especially in kidney cells was distinctly increased by oxaliplatin but not by
BSO-OxMal
. Taken together, our data provide compelling evidence for enhanced tumor specificity of the oxaliplatin(IV)/BSO prodrug.
Platinum(IV) complexes have the potential to overcome several limitations and reduce adverse effects of platinum-based cancer therapy. Resistance to clinically approved platinum(II) drugs is, at least in part, associated with elevated levels of glutathione. Here, the authors report on an oxaliplatin-based platinum(IV) prodrug, which releases
L
-buthionine-
S
,
R
-sulfoximine, an inhibitor of the rate-limiting enzyme in glutathione biosynthesis, to circumvent glutathione-based resistance mechanisms.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
