Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

Helen H.W Chen, Wen Chung Chen, Zhang Dong Liang, Wen Bin Tsai, Yan Long, Isamu Aiba, Siqing Fu, Russell Broaddus, Jinsong Liu, Lynn G. Feun, Niramol Savaraj, Macus Tien Kuo

Research output: Contribution to journalReview article

19 Citations (Scopus)

Abstract

Introduction: Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy.Area covered: Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated.Expert opinion: While both transcriptional and post-translational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed.

Original languageEnglish
Pages (from-to)1307-1317
Number of pages11
JournalExpert Opinion on Therapeutic Targets
Volume19
Issue number10
DOIs
Publication statusPublished - 2015 Oct 3

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Chemotherapy
Drug Delivery Systems
Platinum
Drug Therapy
Copper
Neoplasms
Pharmaceutical Preparations
Cisplatin
Homeostasis
copper transporter 1
Expert Testimony
Chelation
Drug Resistance
Antineoplastic Agents
Ovarian Neoplasms
Biological Availability
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Chen, Helen H.W ; Chen, Wen Chung ; Liang, Zhang Dong ; Tsai, Wen Bin ; Long, Yan ; Aiba, Isamu ; Fu, Siqing ; Broaddus, Russell ; Liu, Jinsong ; Feun, Lynn G. ; Savaraj, Niramol ; Kuo, Macus Tien. / Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy. In: Expert Opinion on Therapeutic Targets. 2015 ; Vol. 19, No. 10. pp. 1307-1317.
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abstract = "Introduction: Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy.Area covered: Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated.Expert opinion: While both transcriptional and post-translational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed.",
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Chen, HHW, Chen, WC, Liang, ZD, Tsai, WB, Long, Y, Aiba, I, Fu, S, Broaddus, R, Liu, J, Feun, LG, Savaraj, N & Kuo, MT 2015, 'Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy', Expert Opinion on Therapeutic Targets, vol. 19, no. 10, pp. 1307-1317. https://doi.org/10.1517/14728222.2015.1043269

Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy. / Chen, Helen H.W; Chen, Wen Chung; Liang, Zhang Dong; Tsai, Wen Bin; Long, Yan; Aiba, Isamu; Fu, Siqing; Broaddus, Russell; Liu, Jinsong; Feun, Lynn G.; Savaraj, Niramol; Kuo, Macus Tien.

In: Expert Opinion on Therapeutic Targets, Vol. 19, No. 10, 03.10.2015, p. 1307-1317.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

AU - Chen, Helen H.W

AU - Chen, Wen Chung

AU - Liang, Zhang Dong

AU - Tsai, Wen Bin

AU - Long, Yan

AU - Aiba, Isamu

AU - Fu, Siqing

AU - Broaddus, Russell

AU - Liu, Jinsong

AU - Feun, Lynn G.

AU - Savaraj, Niramol

AU - Kuo, Macus Tien

PY - 2015/10/3

Y1 - 2015/10/3

N2 - Introduction: Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy.Area covered: Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated.Expert opinion: While both transcriptional and post-translational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed.

AB - Introduction: Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy.Area covered: Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated.Expert opinion: While both transcriptional and post-translational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed.

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