A promising future for breast cancer therapy with hydroxamic acid-based histone deacetylase inhibitors.

in Bioorganic chemistry by Tanima Das, Sunandita Bhar, Diya Ghosh, Bikash Kabi, Kanisha Kar, Arpita Chandra

TLDR

  • The study investigated the role of HA-based HDACi in breast cancer treatment and found promising results in preclinical and clinical studies.
  • The study suggests that targeting HDACs with HA-based HDACi could be a potential therapeutic approach for breast cancer treatment.
  • The study's findings highlight the need for further research to address the challenges faced in the successful clinical application of HDACi.

Abstract

Histone deacetylases (HDACs) play a critical role in chromatin remodelling and modulating the activity of various histone proteins. Aberrant HDAC functions has been related to the progression of breast cancer (BC), making HDAC inhibitors (HDACi) promising small-molecule therapeutics for its treatment. Hydroxamic acid (HA) is a significant pharmacophore due to its strong metal-chelating ability, HDAC inhibition properties, MMP inhibition abilities, and more. They were found to increase the efficacy of the approved drugs when used in combination. In this review we presented bioinformatic analysis using available data from the Cancer Genome Atlas and Genotype-Tissue Expression databases, outlined the recent advancements in the application of HA-based HDACi for BC during preclinical investigation and clinical trials, tried to offer the rationale for targeting HDAC in BC with HA-based HDACi, summarised the challenges faced in the successful clinical application of HDACi, and proposed potential strategies to address these challenges, aiming to enhance treatment outcomes in BC. Abbreviations: ABCG2, ATP-binding cassette super-family G member 2; ABC, ATP-binding cassette; ADP, Adenosine diphosphate; APC, Antigen presenting cell; AML, Acute myeloid leukemia; ARH1, Aplysia ras homolog 1; BCRP, Breast cancer resistance protein; BRCA, Breast invasive carcinoma; Bax, B-cell lymphoma associated X; CK5, Cytokeratin 5; CK14, Cytokeratin 14; CK17, Cytokeratin 17; CoRESTMiDAC, Co-repressor for element-1-silencing transcription factor; CRM1, Chromosomal maintenance 1; CTCL, Cutaneous T-cell lymphoma; DNMT, DNA methyltransferase; DFS, Disease-free survival; ER, Oestrogen receptor; EMT, Epithelial-mesenchymal transition; FGFR1, Fibroblast growth factor receptor 1; GEPIA, Gene Expression Profiling Interactive Analysis; GTEx, Genotype tissue expression; HAT, Histone acetylase; HDAC, Histone deacetylase; HDF, Human dermal fibroblast; HER2, Human epidermal growth factor receptor 2; HDLP, Histone deacetylase-like protein; Hsp90, Heat shock protein 90; HSF1, Heat shock factor 1; HeLa, Henrietta Lacks; HER1, Human epidermal growth factor receptor 1; IARC, International Agency for Research on Cancer; IL-10, Interleukin-10; KAP1, KRAB associated protein 1; MDM2, Mouse double minute 2 homolog; MDR, Multidrug resistance; MCF-7, Michigan cancer foundation-7; MEF-2, Myocyte enhancer factor-2MMP- Matrix metalloproteinase; NAD, Nicotinamide adenine dinucleotide; NuRD, Nucleosome remodelling and deacetylation; NF- κ B, Nuclear factor kappa light chain enhancer of activated B cell; NES, Nuclear export signal; NLS, Nuclear localization signal; NCoR, Nuclear receptor corepressor; NCT, National clinical trial; OS, Overall survival; PR, Progesterone receptor; PI3K, Phosphoinositide 3-kinase; PAX3, Paired box gene 3; P-gp, P-glycoprotein; ROS, Reactive oxygen species; SIRT, Sirtuin; SMRT, Silencing mediator for retinoid and thyroid receptor; STAT3, Signal transducer and activator of transcription-3; SAR, Structure-activity relationship; SHP1, Src homology region 2 domain-containing phosphatase 1; SAHA, Suberoylanilide hydroxamic acid; SMEDDS, Self micro emulsifying drug delivery system; TNBC, Triple-negative breast cancer; TSA, Trichostatin A; ZBG, Zinc binding group.

Overview

  • The study aims to investigate the role of histone deacetylase inhibitors (HDACi) in breast cancer treatment, specifically focusing on hydroxamic acid (HA)-based HDACi.
  • The research employs a bioinformatic analysis of data from the Cancer Genome Atlas and Genotype-Tissue Expression databases, as well as a review of recent preclinical and clinical studies on HA-based HDACi for breast cancer.
  • The study aims to provide a rationale for targeting histone deacetylases (HDACs) in breast cancer using HA-based HDACi and discuss the challenges and potential strategies for their successful clinical application.

Comparative Analysis & Findings

  • The study found that HA-based HDACi have shown promising results in preclinical and clinical studies, increasing the efficacy of approved drugs when used in combination.
  • The data analysis revealed that HDAC inhibition has been associated with the progression of breast cancer, making HDACi a potential therapeutic strategy.
  • The study highlighted the need for further research to address the challenges faced in the successful clinical application of HDACi, including resistance mechanisms and side effects.

Implications and Future Directions

  • The study's findings suggest that targeting HDACs with HA-based HDACi could be a promising therapeutic approach for breast cancer treatment.
  • Future research directions include investigating the use of HA-based HDACi in combination with other therapies and exploring novel delivery methods to improve efficacy and reduce side effects.
  • Addressing the challenges faced in the successful clinical application of HDACi, such as resistance mechanisms and side effects, will be essential for optimizing their clinical potential.
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