Overexpression of human abcb1 and abcg2 reduces the susceptibility of cancer cells to the histone deacetylase 6-specific inhibitor citarinostat

Chung Pu Wu*, Cheng Yu Hung, Sabrina Lusvarghi, Yen Fu Chang, Sung Han Hsiao, Yang Hui Huang, Tai Ho Hung, Jau Song Yu, Suresh V. Ambudkar

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

10 Scopus citations

Abstract

Citarinostat (ACY-241) is a promising oral histone deacetylase 6 (HDAC6)-selective inhibitor currently in clinical trials for the treatment of multiple myeloma (MM) and non-small-cell lung cancer (NSCLC). However, the inevitable emergence of resistance to citarinostat may reduce its clinical effectiveness in cancer patients and limit its clinical usefulness in the future. In this study, we investigated the potential role of the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most common mechanisms of acquired resistance to anticancer drugs, on the efficacy of citarinostat in human cancer cells. We discovered that the overexpression of ABCB1 or ABCG2 significantly reduced the sensitivity of human cancer cells to citarinostat. We demonstrated that the intracellular accumulation of citarinostat and its activity against HDAC6 were substantially reduced by the drug transport function of ABCB1 and ABCG2, which could be restored by treatment with an established inhibitor of ABCB1 or ABCG2, respectively. In conclusion, our results revealed a novel mechanism by which ABCB1 and ABCG2 actively transport citarinostat away from targeting HDAC6 in cancer cells. Our results suggest that the co-administration of citarinostat with a non-toxic modulator of ABCB1 and ABCG2 may optimize its therapeutic application in the clinic.

Original languageEnglish
Article number2592
Pages (from-to)1-14
Number of pages14
JournalInternational Journal of Molecular Sciences
Volume22
Issue number5
DOIs
StatePublished - 01 03 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • ABCB1
  • ABCG2
  • Citarinostat
  • HDAC6
  • Multidrug resistance

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