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

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.

Gemcitabine synergizes with cisplatin to inhibit nasopharyngeal carcinoma cell proliferation and tumor growth

“…ABCB1 (also known as MDR1/multidrug‐resistance 1, P‐gp/P‐glycoprotein) is a plasma membrane protein and first discovered in multidrug‐resistant tumor cells. ABCB1 can extrude a large number of medically relevant compounds from cells and causes drug resistance 50–52 . In this study, we found that the expression of P‐gp is regulated by GEM or DDP or both, and also found that the expression of P‐gp is up‐regulated in both GEM and DDP monodrug‐resistant cell lines, which indicated that P‐gp may play an important role in the combined effect of GEM and DDP, and our follow‐up research will in‐depth explore its function and mechanism in the synergism between GEM and DDP.…”

Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones

“…It is located on the interface of the blood-brain barrier (efflux capacity of the protein protects the central nervous system from compounds with endogenous toxicity), placenta, liver, kidneys, colon and small intestine [ 161 , 162 , 163 , 164 , 165 , 166 , 167 ]. The transporter is involved in decreasing the oral bioavailability, tissue distribution and effectiveness of many therapeutic agents [ 168 ]. ABCG2 transporters are known to be responsible for limited exposure of the brain to anticancer drugs, the effectiveness of which reduces it, especially in case of brain metastases [ 169 ].…”

P-glycoprotein Mediates Resistance to the Anaplastic Lymphoma Kinase Inhibitor Ensartinib in Cancer Cells

“…The intracellular ensartinib was extracted and semi-quantified according to the methods reported in our previous studies [39,43]. Briefly, 2 × 10 6 cells were incubated with 10 µM ensartinib in the absence or presence of 10 µM tariquidar at 37 • C for 60 min and processed as described previously [39,43]. Mobile phase A: 0.1% formic acid in water.…”

“…Knowing that P-gp expression confers resistance to ensartinib, and that one of the most likely explanations for this is the reduced intracellular drug accumulation caused by P-gp-mediated drug efflux [10], we examined the effect of P-gp function on the intracellular accumulation of ensartinib in cancer cells. KB-3-1 and the P-gp-overexpressing variant KB-V1 were treated with 10 µM ensartinib in the absence or presence of 10 µM tariquidar, and the intracellular concentration of ensartinib was determined using a liquid chromatographyselected reaction monitoring mass spectrometry (LC-SRM/MS) method (Figure 3a) as described previously [39,41,43]. Human KB epidermal cancer cell lines were chosen for this study since KB-V1 showed the highest RF value among all the P-gp-overexpressing cell lines (Table 1).…”