Abstract
Platinum drugs are an important class of cancer chemotherapeutics. However, the use of these drugs is limited by the development of resistance during treatment with decreased accumulation being a common mechanism. Both Cu transporters CTR1 and CTR2 influence the uptake and cytotoxicity of cisplatin. Although it is structurally similar to CTR1, CTR2 functions in a manner opposite to that of CTR1 with respect to Pt drug uptake. Whereas knockout of CTR1 reduces Pt drug uptake, knockdown of CTR2 enhances cisplatin uptake and cytotoxicity. CTR2 is subject to transcriptional and posttranscriptional regulation by both Cu and cisplatin; this regulation is partly dependent on the Cu chaperone ATOX1. Insight into the mechanisms by which CTR1 and CTR2 regulate sensitivity to the Pt-containing drugs has served as the basis for novel pharmacologic strategies for improving their efficacy.
Highlights
Platinum- (Pt-) based chemotherapeutic agents have been utilized in the treatment malignancies since their first approval in the 1970s
This short paper will focus on recent developments in understanding how the cellular pharmacology of the Pt-containing drugs is influenced by proteins belonging to the Cu homeostasis system with an emphasis on the Cu transporter (CTR) family and Cu transporter 2 (CTR2) in particular
Many of the proteins involved in Cu homeostasis influence the uptake and cytotoxicity of the Pt-containing drugs [1, 21, 53], and cisplatin has been shown to interact with several of these including the efflux pump ATP7B [54]
Summary
Platinum- (Pt-) based chemotherapeutic agents have been utilized in the treatment malignancies since their first approval in the 1970s. Decreased accumulation is one of the most commonly observed features observed in resistant tumor cells both in vitro and in vivo, and there are multiple lines of evidence indicating that proteins involved in Cu homeostasis are responsible for the import, intracellular distribution, and export of the various Pt agents [1]. This short paper will focus on recent developments in understanding how the cellular pharmacology of the Pt-containing drugs is influenced by proteins belonging to the Cu homeostasis system with an emphasis on the Cu transporter (CTR) family and Cu transporter 2 (CTR2) in particular
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