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

Carl T. Gustafson, Tewodros Mamo, Avudaiappan Maran, Michael J Yaszemski

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Osteosarcoma is the most common bone tumor that affects children and young adults. Despite advances in the use of combination chemotherapy regimens, response to neoadjuvant chemotherapy in osteosarcoma remains a key determinant of patient outcome. Recently, highly potent small molecule inhibitors of canonical Wnt signaling through the poly(ADP-ribose) polymerase (PARP)-family enzymes, tankyrases 1 & 2 (Tnks1/2), have been considered as possible chemotherapy sensitizing agents. The goal of this study was to determine the ability of the highly specific Tnks1/2 inhibitor IWR-1-endo to sensitize chemotherapy-resistant osteosarcoma to doxorubicin. We found that IWR-1-endo significantly inhibited cellular efflux, as measured by cellular retention of Calcein AM and doxorubicin. In a model of doxorubicin resistant osteosarcoma, pre-treatment with IWR-1-endo strongly sensitized to doxorubicin. This sensitization reduced the doxorubicin IC50 in doxorubicin-resistant cells, but not in chemotherapy naïve cells and caused doxorubicin-treated cells to accumulate at the G2/M checkpoint. Further, we found that sensitization with IWR-1-endo produced increased γH2AX foci formation, indicating increased DNA damage by doxorubicin. Taken together, our findings show that IWR-1-endo increases cellular responses to doxorubicin, by blocking efflux transport in a drug-resistant model of osteosarcoma.

Original languageEnglish (US)
Pages (from-to)141-149
Number of pages9
JournalBiochemical Pharmacology
Volume150
DOIs
StatePublished - Apr 1 2018

Keywords

  • Doxorubicin
  • Efflux transport
  • Multidrug resistance protein 1
  • Tankyrase inhibitor
  • Wnt signaling

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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