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Efflux inhibition by IWR-1-endo confers sensitivity to doxorubicin effects in osteosarcoma cells

Carl T Gustafson1, Tewodros Mamo1, Avudaiappan Maran2

  • 1Mayo Clinic College of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.

Biochemical Pharmacology
|February 8, 2018
PubMed

Insights

A novel drug, IWR-1-endo, sensitizes chemotherapy-resistant osteosarcoma to doxorubicin by blocking drug efflux. This approach enhances DNA damage and improves treatment response in resistant bone cancer models.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Osteosarcoma is a prevalent bone tumor in children and young adults.
  • Chemotherapy response is critical for osteosarcoma patient outcomes.
  • Wnt signaling inhibitors, like tankyrase inhibitors, are explored for chemotherapy sensitization.

Purpose of the Study:

  • To evaluate if the tankyrase inhibitor IWR-1-endo can sensitize chemotherapy-resistant osteosarcoma to doxorubicin.
  • To investigate the mechanisms by which IWR-1-endo affects drug response in osteosarcoma.

Main Methods:

  • Utilized a doxorubicin-resistant osteosarcoma cell model.
  • Measured cellular drug efflux using Calcein AM and doxorubicin retention assays.
  • Assessed drug sensitivity (IC50), cell cycle progression (G2/M checkpoint), and DNA damage (γH2AX foci).

Main Results:

  • IWR-1-endo significantly inhibited cellular efflux of doxorubicin.
  • Pre-treatment with IWR-1-endo sensitized doxorubicin-resistant osteosarcoma cells to doxorubicin, lowering the IC50.
  • Sensitization led to G2/M cell cycle arrest and increased doxorubicin-induced DNA damage (γH2AX foci).

Conclusions:

  • IWR-1-endo enhances doxorubicin efficacy in resistant osteosarcoma by blocking drug efflux.
  • This strategy shows potential for overcoming chemotherapy resistance in osteosarcoma.
  • Targeting tankyrases may represent a viable approach to improve osteosarcoma treatment outcomes.
Keywords:
DoxorubicinEfflux transportMultidrug resistance protein 1Tankyrase inhibitorWnt signaling

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