Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐...

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Published inMedicinal research reviews Vol. 41; no. 1; pp. 525 - 555
Main Authors Zhang, Hang, Xu, Haiwei, Ashby, Charles R., Assaraf, Yehuda G., Chen, Zhe‐Sheng, Liu, Hong‐Min
Format Journal Article
LanguageEnglish
Published United States Wiley Subscription Services, Inc 01.01.2021
Subjects
cancer
Cancer therapies
Chemotherapy
Drug resistance
Glycoproteins
mechanism of action
multidrug resistance (MDR)
Multidrug resistant organisms
pharmacological characterization
P‐glycoprotein (P‐gp) inhibitors
structure‐activity relationship (SAR) studies
pharmacological characterization
P-glycoprotein (P-gp) inhibitors
mechanism of action
multidrug resistance (MDR)
structure-activity relationship (SAR) studies
cancer
chemotherapy
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Abstract Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR.
AbstractList Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP-binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P-glycoprotein (P-gp/ABCB1) has been most well-established. The clinical co-administration of P-gp drug efflux inhibitors, in combination with anticancer drugs which are P-gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P-gp-mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P-gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure-activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P-gp inhibitors in the past 5 years. The development of P-gp inhibitors will increase our knowledge of the mechanisms and functions of P-gp-mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P-gp transporter overexpression has been implicated in MDR.Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP-binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P-glycoprotein (P-gp/ABCB1) has been most well-established. The clinical co-administration of P-gp drug efflux inhibitors, in combination with anticancer drugs which are P-gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P-gp-mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P-gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure-activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P-gp inhibitors in the past 5 years. The development of P-gp inhibitors will increase our knowledge of the mechanisms and functions of P-gp-mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P-gp transporter overexpression has been implicated in MDR.
Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ ABCB1 ) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR.
Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR.
Author Assaraf, Yehuda G.
Chen, Zhe‐Sheng
Zhang, Hang
Xu, Haiwei
Liu, Hong‐Min
Ashby, Charles R.
Author_xml – sequence: 1
  givenname: Hang
  surname: Zhang
  fullname: Zhang, Hang
  organization: Zhengzhou University
– sequence: 2
  givenname: Haiwei
  surname: Xu
  fullname: Xu, Haiwei
  organization: Zhengzhou University
– sequence: 3
  givenname: Charles R.
  surname: Ashby
  fullname: Ashby, Charles R.
  organization: St. John's University
– sequence: 4
  givenname: Yehuda G.
  surname: Assaraf
  fullname: Assaraf, Yehuda G.
  organization: The Fred Wyszkowski Cancer Research Laboratory, Technion‐Israel Institute of Technology
– sequence: 5
  givenname: Zhe‐Sheng
  orcidid: 0000-0002-8289-097X
  surname: Chen
  fullname: Chen, Zhe‐Sheng
  email: chenz@stjohns.edu
  organization: St. John's University
– sequence: 6
  givenname: Hong‐Min
  orcidid: 0000-0001-6771-9421
  surname: Liu
  fullname: Liu, Hong‐Min
  email: liuhm@zzu.edu.cn
  organization: Zhengzhou University
BackLink https://www.ncbi.nlm.nih.gov/pubmed/33047304$$D View this record in MEDLINE/PubMed
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Issue 1
Keywords pharmacological characterization
P-glycoprotein (P-gp) inhibitors
mechanism of action
multidrug resistance (MDR)
structure-activity relationship (SAR) studies
cancer
chemotherapy
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Snippet Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by...
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SubjectTerms cancer
Cancer therapies
Chemotherapy
Drug resistance
Glycoproteins
mechanism of action
multidrug resistance (MDR)
Multidrug resistant organisms
pharmacological characterization
P‐glycoprotein (P‐gp) inhibitors
structure‐activity relationship (SAR) studies
Title Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fmed.21739
https://www.ncbi.nlm.nih.gov/pubmed/33047304
https://www.proquest.com/docview/2469805729
https://www.proquest.com/docview/2450650722
Volume 41
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