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Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
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ATP-binding cassette or ABC transporter is the largest superfamily of integral membrane proteins. The transporters have transmembrane-binding domains (TMDs) and nucleotide-binding domains (NBDs). The TMDs are specific to their substrates, whereas the NBDs are similar to engines that complete ATP hydrolysis to complete the substrate transport. They can be full transporters consisting of two TMDs and NBDs, half transporters with one TMD and NBD, while some encoded with a single TMD or NBD are...
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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells.

Zhuo-Xun Wu1, Zheng Peng2, Yuqi Yang1

  • 1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

Frontiers in Oncology
|June 2, 2020
PubMed
Summary
This summary is machine-generated.

M3814, a DNA-dependent protein kinase inhibitor, can overcome multidrug resistance (MDR) by modulating the ABCG2 transporter. This drug enhances the accumulation of chemotherapy drugs, offering a new strategy for cancer treatment.

Keywords:
ABCG2ATP-binding cassette (ABC) transporterM3814multidrug resistance (MDR)nedisertib

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cancer Research

Background:

  • Multidrug resistance (MDR) in cancer is often mediated by ATP-binding cassette (ABC) transporters, such as ABCG2.
  • Overcoming ABCG2-mediated MDR is crucial for improving cancer treatment efficacy.

Purpose of the Study:

  • To investigate the effect of M3814 (nedisertib), a DNA-dependent protein kinase (DNA-PK) inhibitor, on ABCG2 transporter function.
  • To determine if M3814 can overcome ABCG2-mediated multidrug resistance.

Main Methods:

  • In vitro studies assessing ABCG2 transporter activity and drug efflux.
  • Analysis of ABCG2 protein expression and cell surface localization.
  • Molecular docking to predict M3814 binding to ABCG2.

Main Results:

  • M3814 attenuates the efflux activity of the ABCG2 transporter.
  • M3814 increases the intracellular accumulation of ABCG2 substrate drugs.
  • M3814 stimulates ABCG2 ATPase activity without altering protein expression or localization.
  • Molecular docking confirms high affinity binding of M3814 to the ABCG2 drug-binding cavity.

Conclusions:

  • M3814 acts as an ABCG2 modulator, effectively overcoming ABCG2-mediated MDR.
  • Co-administration of M3814 with ABCG2 substrate drugs presents a potential therapeutic strategy to enhance cancer treatment outcomes.