Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan.
Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan.
Int J Mol Sci. 2021 Mar 5;22(5):2592. doi: 10.3390/ijms22052592.
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.
西达本胺（ACY-241）是一种有前景的口服组蛋白去乙酰化酶 6（HDAC6）选择性抑制剂，目前正在进行多发性骨髓瘤（MM）和非小细胞肺癌（NSCLC）的临床试验。然而，西达本胺不可避免地会出现耐药性，这可能会降低其在癌症患者中的临床疗效，并限制其未来的临床应用。在这项研究中，我们研究了多药外排转运蛋白 ABCB1 和 ABCG2 的潜在作用，它们是癌症药物获得性耐药的两种最常见机制之一，对西达本胺在人癌细胞中的疗效的影响。我们发现，ABCB1 或 ABCG2 的过表达显著降低了人癌细胞对西达本胺的敏感性。我们证明，ABCB1 和 ABCG2 的药物转运功能显著降低了西达本胺的细胞内积累及其对 HDAC6 的活性，这可以分别通过用已建立的 ABCB1 或 ABCG2 抑制剂处理来恢复。总之，我们的结果揭示了 ABCB1 和 ABCG2 主动将西达本胺从癌细胞中靶向 HDAC6 转运出去的新机制。我们的结果表明，西达本胺与 ABCB1 和 ABCG2 的非毒性调节剂联合使用可能会优化其在临床上的治疗应用。
