Abstract
Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting—carried out by the high-affinity copper (Cu) transporter (hCtr1), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively—cumulatively contribute to the chemosensitivity of Pt drugs including cisplatin and carboplatin, but not oxaliplatin. This entire system can also handle Pt drugs via interactions between Pt and the thiol-containing amino acid residues in these proteins; the interactions are strongly influenced by cellular redox regulators such as glutathione. hCtr1 expression is induced by acute Cu deprivation, and the induction is regulated by the transcription factor specific protein 1 (Sp1) which by itself is also regulated by Cu concentration variations. Copper displaces zinc (Zn) coordination at the zinc finger (ZF) domains of Sp1 and inactivates its DNA binding, whereas Cu deprivation enhances Sp1-DNA interactions and increases Sp1 expression, which in turn upregulates hCtr1. Because of the shared transport system, chemosensitivity of Pt drugs can be modulated by targeting Cu transporters. A Cu-lowering agent (trientine) in combination with a Pt drug (carboplatin) has been used in clinical studies for overcoming Pt-resistance. Future research should aim at further developing effective Pt drug retention strategies for improving the treatment efficacy.
Highlights
Platinum (Pt)-based drugs represent an extraordinary accomplishment in antitumor inorganic metal drug development [1]
In 40 ovarian cancers, it was reported that while high human Ctr1 (hCtr1) expression is associated with chemosensitivity of Pt-based drugs, patients with low hCtr1 and high hCtr2 in their tumors have poor treatment outcomes and shorter overall survival (OS) time [28]. It reported that ovarian cancer patients with high hCtr2/hCtr1 ratios in the tumor lesions are resistant to Pt-based chemotherapy [29]. These results demonstrated that hCtr2, in conjunction with hCtr1, may involve in chemosensitivity of Pt drugs
Pt drugs have been effective in treating many human malignancies, treatment efficacy has been hampered by drug resistance
Summary
Platinum (Pt)-based drugs represent an extraordinary accomplishment in antitumor inorganic metal drug development [1]. [4] and references therein), but DNA damages are the principle cause of Pt druginduced cell lethality Another important factor that affects the treatment efficacy is the transport system which includes drug accumulation, intracellular andThis drugsystem effluxcumulatively (Figure 1A). These observations demonstrated that distribution, and export of Pt drugs [3] These observations demonstrated that Cu. Cu ions ions and and cDDP share similar transport mechanisms and mutually interfere with their cellular accumulations. In share similar transport mechanisms and mutually interfere with their cellular accumulations In this this review, we will will first first discuss discuss the the underlying underlying mechanisms mechanisms of of how how the the Cu. Pt drugs drugs from intracellular trafficking, trafficking, and and exiting exiting the the cells
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