Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition

You, Dahea; Richardson, Jason; Aleksunes, Lauren M.

doi:10.1124/dmd.119.089953

Cited by 22 publications

(10 citation statements)

References 366 publications

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“…Epigenetic dysfunction has been reported in breast cancer [8], and targeting epigenetic abnormalities with various modulators has shown anti-cancer efficacy in vivo and in vitro [9][10][11]. Histone deacetylases (HDACs), which remove the acetyl groups from lysines that have been N-acetylated by histone acetylases, target epigenetic changes in tumors and alter gene regulation; they have recently become important targets for anti-tumor drug design [12].…”

Section: Introductionmentioning

confidence: 99%

Phase I Study and Pilot Efficacy Analysis of Entinostat, a Novel Histone Deacetylase Inhibitor, in Chinese Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer

Wang

Zhang

et al. 2021

Targ Oncol

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Background Previous clinical trials have demonstrated that entinostat in combination with exemestane had good tolerability and significant clinical efficacy in patients with advanced hormone receptor positive (HR+) and HER2 negative (HER2−) metastatic breast cancer (MBC) in the USA. However, no clinical trials have been conducted in Chinese populations. Objective To investigate the safety, pharmacokinetics, and pilot efficacy of entinostat with or without exemestane in Chinese postmenopausal patients with locally advanced or metastatic HR+ /HER2− MBC. Patients and methods Nineteen patients received entinostat for 4 weeks (dose-limiting toxicity (DLT) observation stage) at 3, 5, or 7 mg/week, with a "3+3" dose-escalation design and in combination with exemestane thereafter (extended treatment stage: entinostat, 3 or 5 mg/week; exemestane, 25 mg/day). An additional 21 patients were enrolled to assess the entinostat (5 mg) plus exemestane (25 mg) pharmacokinetic profile and potential efficacy. Results The peak entinostat serum concentration and area under the curve increased dose proportionally, without significant interaction between entinostat and exemestane. Entinostat was well tolerated at all doses. The most common grade 3/4 adverse effects (AEs) included neutropenia (31.6%) and thrombocytopenia (15.8%). In the DLT observation stage, grade 3/4 AEs accounted for 16.7% in the 5 mg group with one suspicious DLT (G3 ventricular tachycardia) and 33.3% in the 7 mg group. In the extended treatment stage, 2/16 patients achieved partial response and three patients experienced stable disease (> 12 weeks). The median progression-free survival was 9.41 months for the additional 21 patients, who experienced grade 3/4 AEs of neutropenia (38%), thrombocytopenia (9.5%), anemia (9.5%), and fatigue (9.5%). Conclusion Entinostat with exemestane showed reasonable safety, tolerability, and encouraging efficacy in Chinese patients with HR+/HER2− MBC. These results support further evaluation in a randomized, double-blind Phase III study with a weekly 5 mg entinostat dose in a Chinese population. Trial Registration NCT02833155.

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Section: Introductionmentioning

confidence: 99%

Phase I Study and Pilot Efficacy Analysis of Entinostat, a Novel Histone Deacetylase Inhibitor, in Chinese Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer

Wang

Zhang

et al. 2021

Targ Oncol

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“…A total of 98 small molecules that possess P-glycoprotein-inhibiting properties were approved by the FDA, with indications for non-cancer diseases [ 23 ]. Novel strategies to limit or reverse multidrug resistance include miRNA, DNA methyltransferase inhibitors (DNMTis), hypomethylating agents (HMAs), and histone deacetylase inhibitors (HDACis) [ 24 ], but HDAC inhibitors elicit divergent responses in drug-sensitive and resistant cancer cells [ 25 ]. HDAC inhibitors are usually associated with the activation of gene transcription because they prevent histone deacetylation, but numerous other HDAC non-histone HDAC targets have different impacts on gene transcription depending on their acetylation statuses.…”

Section: Discussionmentioning

confidence: 99%

CBP/p300 Bromodomain Inhibitor–I–CBP112 Declines Transcription of the Key ABC Transporters and Sensitizes Cancer Cells to Chemotherapy Drugs

Strachowska

Gronkowska

Michlewska

et al. 2021

Cancers

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The high expression of some ATP-binding cassette (ABC) transporters is linked to multidrug resistance in cancer cells. We aimed to determine if I-CBP112, which is a CBP/p300 bromodomain inhibitor, altered the vulnerability of the MDA-MB-231 cell line to chemotherapy drugs, which are used in neoadjuvant therapy in patients with triple negative breast cancer (TNBC). MDA-MB-231 cells represent TNBC, which is negative for the expression of estrogen and progesterone receptors and HER2 protein. An I-CBP112-induced decrease in the expression of all the studied ABCs in the breast, but also in the lung (A549), and hepatic (HepG2) cancer cell lines was associated with increased accumulation of doxorubicin, daunorubicin, and methotrexate inside the cells as well as considerable cell sensitization to a wide range of chemotherapeutics. Gene promoters repressed by I-CBP112 in MDA-MB-231 cells, such as ABCC1 and ABCC10, were characterized by enhanced nucleosome acetylation and, simultaneously, by considerably lower trimethylation in the transcription-promoting form of H3K4me3. The CBP/p300 bromodomain inhibitor induced the recruitment of LSD1 to the gene promoters, and the inhibition of this demethylase in the presence of I-CBP112 prevented the repression of ABCC1 and ABCC10 and, to a considerable extent, cancer cells’ sensitization to drugs. In conclusion, the CBP/p300 bromodomain inhibitor I-CBP112 can be considered as a potent anti-multidrug-resistance agent, capable of repressing key ABC transporters responsible for drug efflux in various cancer types.

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“…Histone acetylation is an epigenetic modification that can regulate gene expression by changing the accessibility of the genome to transcriptional regulators and transcriptional machinery [ 26 ]. Previous studies have suggested that the pharmacological inhibition of histone deacetylases (HDACs) modulates the expression and function of Pgp and BCRP as a result of enhanced histone acetylation [ 27 ]. In an in vitro model of the human BBB, the human BCEC line hCMEC/D3 (Human Cerebral Microvascular Endothelial Cell Line clonal population D3), enhanced histone acetylation in response to HDAC inhibitors increased ABCB1 mRNA and Pgp protein levels and Pgp transport activity [ 28 ].…”

Section: Regulation Of Pgp At the Bbb: Conventional Mechanismsmentioning

confidence: 99%

Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

Löscher

Gericke

2020

Pharmaceutics

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The blood–brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to drug delivery into the brain. Here, we review the complex regulation of Pgp expression and functional activity at the BBB with an emphasis on recent studies from our laboratory. In addition to traditional processes such as transcriptional regulation and posttranscriptional or posttranslational modification of Pgp expression and functionality, novel mechanisms such as intra- and intercellular Pgp trafficking and intracellular Pgp-mediated lysosomal sequestration in BBB endothelial cells with subsequent disposal by blood neutrophils are discussed. These intrinsic mechanisms of active drug extrusion at the BBB are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the treatment of brain diseases and enhance drug delivery to the brain.

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Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition

Cited by 22 publications

References 366 publications

Phase I Study and Pilot Efficacy Analysis of Entinostat, a Novel Histone Deacetylase Inhibitor, in Chinese Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer

Phase I Study and Pilot Efficacy Analysis of Entinostat, a Novel Histone Deacetylase Inhibitor, in Chinese Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer

CBP/p300 Bromodomain Inhibitor–I–CBP112 Declines Transcription of the Key ABC Transporters and Sensitizes Cancer Cells to Chemotherapy Drugs

Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

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