Overexpression of Human ABCB1 and ABCG2 Reduces the Susceptibility of Cancer Cells to the Histone Deacetylase 6-Specific Inhibitor Citarinostat.

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

doi:10.3390/ijms22052592

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.

Highlights

Our study revealed that the drug transport mediated by ABCB1 or ABCG2 represents a novel mechanism for acquired resistance to citarinostat in human cancer cells; combination therapies will need to be tested to overcome this clinical problem in the future
To examine the effect of ABCB1 and ABCG2 on the chemosensitivity of human cancer cell lines to citarinostat, we determined the cytotoxicity of citarinostat in multiple pairs of ABCB1- or ABCG2-overexpressing multidrug-resistant cancer cell lines and the respective drug-sensitive parental lines
We first noticed that citarinostat was significantly more cytotoxic to the parental human KB-3-1 epidermal cancer cells and the parental human S1 colon cancer cells than to the respective ABCB1-overexpressing variant KB-V-1

Summary

Introduction

Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups from the acetylated histone and non-histone proteins, leading to chromatin condensation and transcriptional repression [1]. Non-selective panHDAC inhibitors panobinostat (LBH589) and belinostat (PXD101) have been approved by the U.S Food and Drug Administration (FDA) for use in patients with multiple myeloma (MM) [5] and relapsed or refractory peripheral T-cell lymphoma [6], respectively. Researchers have been developing isotype-selective HDAC inhibitors, such as ricolinostat (ACY-1215), that target class IIb HDAC relative to class I HDACs [14,15,16,17,18,19,20,21]. The class IIb HDAC, HDAC6, is localized predominantly within the cytoplasm and deacetylates non-histone substrates such as α-tubulin and heat shock protein 90 (Hsp90) [22,23,24]

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