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AZ32 Reverses ABCG2-Mediated Multidrug Resistance in Colorectal Cancer

Kun Liu1, Yan-Chi Li1, Yu Chen1

  • 1Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China.

Frontiers in Oncology
|June 7, 2021
PubMed

Insights

AZ32, an ATM kinase inhibitor, effectively reverses multidrug resistance (MDR) in colorectal cancer cells overexpressing ABCG2. This novel approach enhances chemotherapy efficacy by retaining drugs within cancer cells, offering a promising strategy against treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Colorectal cancer presents a significant global health challenge, with chemotherapy resistance contributing to high mortality rates.
  • The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) transporter is a key mediator of multidrug resistance (MDR) in cancer by effluxing chemotherapeutic agents.
  • Developing effective ABCG2 inhibitors is crucial for overcoming drug resistance in colorectal cancer treatment.

Purpose of the Study:

  • To investigate the potential of ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 in reversing ABCG2-mediated multidrug resistance in colorectal cancer.
  • To evaluate AZ32's effect on the intracellular retention of chemotherapeutic drugs in ABCG2-overexpressing colorectal cancer cells.

Main Methods:

  • Establishment of an ABCG2-knockout colorectal cancer cell line for inhibitor screening.
  • Treatment of ABCG2-overexpressing cells with AZ32 and chemotherapeutic drugs (mitoxantrone, doxorubicin).
  • Western blot analysis to assess ABCG2 expression levels and molecular docking to predict AZ32's binding site within ABCG2.

Main Results:

  • AZ32 sensitized ABCG2-overexpressing colorectal cancer cells to mitoxantrone and doxorubicin, increasing their intracellular retention.
  • AZ32 treatment did not affect the expression levels of the ABCG2 transporter.
  • Molecular docking simulations indicated that AZ32 binds to the transmembrane domain of ABCG2.

Conclusions:

  • AZ32 demonstrates potent activity in reversing ABCG2-mediated multidrug resistance in colorectal cancer.
  • AZ32 acts by retaining ABCG2 substrate drugs within cancer cells, independent of altering ABCG2 expression.
  • This study highlights AZ32 as a promising therapeutic agent to overcome chemotherapy resistance in colorectal cancer.
Keywords:
ABCG2AZ32CRISPRcolorectal cancermultidrug resistance

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