Current trends in development of HDAC-based chemotherapeutics

Cheshmazar, Narges; Hamzeh‐Mivehroud, Maryam; Charoudeh, Hojjatollah Nozad; Hemmati, Salar; Melesina, Jelena; Dastmalchi, Siavoush

doi:10.1016/j.lfs.2022.120946

Cited by 22 publications

(11 citation statements)

References 67 publications

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“…Nonspecific inhibitors of epigenetic abnormalities are effective drugs. These include inhibitors of HDACs, BRDs, HATs, and components of PRCs; 216–219 several studies have reported the potential efficacy of these inhibitors. Epigenome‐editing‐based cancer therapy modulates the expression of critical targets regardless of their mutational status.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

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Targeting epigenetic aberrations of sarcoma in CRISPR era

Tanaka

Nakamura

2023

Genes Chromosomes & Cancer

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Sarcomas are rare malignancies that exhibit diverse biological, genetic, morphological, and clinical characteristics. Genetic alterations, such as gene fusions, mutations in transcriptional machinery components, histones, and DNA methylation regulatory molecules, play an essential role in sarcomagenesis. These mutations induce and/or cooperate with specific epigenetic aberrations required for the growth and maintenance of sarcomas. Appropriate mouse models have been developed to clarify the significance of genetic and epigenetic interactions in sarcomas. Studies using the mouse models for human sarcomas have demonstrated major advances in our understanding the developmental processes as well as tumor microenvironment of sarcomas. Recent technological progresses in epigenome editing will not only improve the studies using animal models but also provide a direct clue for epigenetic therapies. In this manuscript, we review important epigenetic aberrations in sarcomas and their representative mouse models, current methods of epigenetic editing using CRISPR/ dCas9 systems, and potential applications in sarcoma studies and therapeutics.

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Section: Summary and Future Directionsmentioning

confidence: 99%

“…Nonspecific inhibitors of epigenetic abnormalities are effective drugs. These include inhibitors of HDACs, BRDs, HATs, and components of PRCs; [216][217][218][219] several studies have reported the potential efficacy of these inhibitors.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Targeting epigenetic aberrations of sarcoma in CRISPR era

Tanaka

Nakamura

2023

Genes Chromosomes & Cancer

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“…6 As HDACs are usually aberrantly regulated in drug refractory cancer, they represent novel therapeutic targets to overcome chemoresistance. 7 To date, four HDAC inhibitors (HDACIs) (vorinostat (SAHA), romidepsin, belinostat, and panobinostat) are clinically approved for cancer treatment by major drug regulatory authorities. 7 Drug combinations with HDACIs are considered a promising strategy to overcome chemoresistance.…”

mentioning

confidence: 99%

“…Moreover, HDACs also regulate various nonhistone proteins important for cancer development . As HDACs are usually aberrantly regulated in drug refractory cancer, they represent novel therapeutic targets to overcome chemoresistance . To date, four HDAC inhibitors (HDACIs) (vorinostat (SAHA), romidepsin, belinostat, and panobinostat) are clinically approved for cancer treatment by major drug regulatory authorities .…”

mentioning

confidence: 99%

“…As HDACs are usually aberrantly regulated in drug refractory cancer, they represent novel therapeutic targets to overcome chemoresistance . To date, four HDAC inhibitors (HDACIs) (vorinostat (SAHA), romidepsin, belinostat, and panobinostat) are clinically approved for cancer treatment by major drug regulatory authorities . Drug combinations with HDACIs are considered a promising strategy to overcome chemoresistance. , Extensive preclinical and clinical research about these novel drug combinations has been conducted with promising findings. , HDACIs were reported to modulate pro-apoptotic and cell cycle regulatory genes to elicit their anticancer activities …”

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confidence: 99%

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Circumvention of Gefitinib Resistance by Repurposing Flunarizine via Histone Deacetylase Inhibition

To,

Chow,

Cheung

et al. 2023

ACS Pharmacol. Transl. Sci.

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Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) for treating advanced nonsmall cell lung cancer (NSCLC). However, drug resistance seriously impedes the clinical efficacy of gefitinib. This study investigated the repositioning of the non-oncology drug capable of inhibiting histone deacetylases (HDACs) to overcome gefitinib resistance. A few drug candidates were identified using the in silico repurposing tool "DRUGSURV" and tested for HDAC inhibition. Flunarizine, originally indicated for migraine prophylaxis and vertigo treatment, was selected for detailed investigation in NSCLC cell lines harboring a range of different gefitinib resistance mechanisms (EGFR T790M, KRAS G12S, MET amplification, or PTEN loss). The circumvention of gefitinib resistance by flunarizine was further demonstrated in an EGFR TKI (erlotinib)-refractory patient-derived tumor xenograft (PDX) model in vivo. The acetylation level of cellular histone protein was increased by flunarizine in a concentration-and time-dependent manner. Among the NSCLC cell lines evaluated, the extent of gefitinib resistance circumvention by flunarizine was found to be the most pronounced in EGFR T790Mbearing H1975 cells. The gefitinib−flunarizine combination was shown to induce the apoptotic protein Bim but reduce the antiapoptotic protein Bcl-2, which apparently circumvented gefitinib resistance. The induction of Bim by flunarizine was accompanied by an increase in the histone acetylation and E2F1 interaction with the BIM gene promoter. Flunarizine was also found to upregulate E-cadherin but downregulate the vimentin expression, which subsequently inhibited cancer cell migration and invasion. Importantly, flunarizine was also shown to significantly potentiate the tumor growth suppressive effect of gefitinib in EGFR TKIrefractory PDX in vivo. The findings advocate for the translational application of flunarizine to circumvent gefitinib resistance in the clinic.

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Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor‐associated immune suppressive cells

Tang,

Cui,

Liu

et al. 2024

Cancer Communications

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Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called “cold” tumors which are unresponsive to immunotherapy, and the opposite are “hot” tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor‐associated macrophages (TAMs), myeloid‐derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of “cold” tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming “cold” tumors into “hot” tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy‐insensitive tumors into immunotherapy‐sensitive tumors which would be an innovative tendency for future immunotherapy in “cold” tumor.

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Current trends in development of HDAC-based chemotherapeutics

Cited by 22 publications

References 67 publications

Targeting epigenetic aberrations of sarcoma in CRISPR era

Targeting epigenetic aberrations of sarcoma in CRISPR era

Circumvention of Gefitinib Resistance by Repurposing Flunarizine via Histone Deacetylase Inhibition

Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor‐associated immune suppressive cells

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