4.6 Review

Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy

期刊

PHARMACEUTICALS
卷 14, 期 6, 页码 -

出版社

MDPI
DOI: 10.3390/ph14060549

关键词

cisplatin; carboplatin; oxaliplatin; copper transporter; Ctr1; Atox1; ATP7A; ATP7B; Sp1; copper chelator

资金

  1. Center of Applied Nanomedicine, National Cheng Kung University from The Featured Areas Research Center Program within the Ministry of Education (MOE) in Taiwan
  2. National Research Program for Biopharmaceuticals (NRPB)
  3. National Science Council, Taiwan [NSC101-2325-B-006-022, NSC102-2325-B-006-020, NSC103-2325-B-006-006]
  4. Ministry of Science and Technology, Taiwan [MOST 108-2314-B-006-061-MY2, MOST-108-2314-B-006-019-MY3]

向作者/读者索取更多资源

Platinum-containing antitumor drugs, such as cisplatin, carboplatin, and oxaliplatin, have been effective in treating various human malignancies by targeting DNA. Recent research emphasizes the significance of the copper transport system in cancer therapy. Modulating cellular copper levels can impact the transport and efficacy of platinum-based chemotherapy drugs.
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.

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