Abstract
The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs.
Highlights
Platinum (Pt)-based antitumor agents, including cisplatin, carboplatin, and oxaliplatin, are active against many tumor types. cDDP is commonly used for treating metastatic testicular cancer, carboplatin for advanced ovarian cancer, and oxaliplatin for advanced colorectal cancer. cDDP has been used for treating other cancers, including cancers of lung, bladder, head, and neck, and uterine cervix [1,2]
We previously reported that specificity protein 1 (Sp1) is the transcription factor that regulates hCtr1 expression in response to Cu conditions [92,93]
Pt-based drugs represent an extraordinary accomplishment in inorganic antitumor drug development [2]
Summary
The use of cDDP is limited by its adverse side effects including nephrotoxicity [3,4], ototoxicity [4], and peripheral neurotoxicity These toxicities are not associated with carboplatin, which mainly induces myelosuppression; whereas the most common toxicity associated with oxaliplatin is peripheral neuropathy [5]. The cytotoxic target of these drugs is DNA, by forming primarily intra-stranded crosslinks d(GpG) adducts. If not repaired, these lesions will damage DNA replication, transcription, and associated cellular functions, resulting in cell death or apoptosis. Pharmaceuticals 2021, 14, 549 are the hallmark of Pt-drug resistance [7] These findings strongly suggest that Pt drug transport mechanisms play important roles in cell-killing of Pt-based antitumor agents. Pt drug cancer chemotherapy by targeting the Cu transport system in cultured cell models and in clinical settings
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