Histone deacetylase inhibitors – molecular mechanisms of actions and clinical applications

Abstract

Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression implicated in cancer pathogenesis. Inhibitors of HDACs (HDI) are under investigation as novel anti-cancer drugs, which induce histone hyperacetylation. These agents modulate chromatin structure leading to transcriptional changes of a very large number of genes, which affect signaling pathways, inhibit cell cycle progression and angiogenesis, and induce apoptosis in cancer cells. Currently, several HDI are in clinical trials used in monotherapy or in combination with other cytostatics, showing promising anticancer effects. To date, more than 15 HDIs have been found as potential drugs. This paper reviews the molecular mechanisms of HDI action on cancer cells and summarizes clinical trials of the most promising HDIs in the treatment of patients with hematologic malignancies and solid tumors.

Next-generation of selective histone deacetylase inhibitors

“…Importantly, the high expression of HDACs were found in several types of cancers. 45,46 For instance, transcriptional upregulation of HDAC1 is observed in colorectal and pancreatic cancers. In addition, HDAC3 in lung and colon cancers, HDAC8 in neuroblastoma were also found to be overexpressed.…”

Differential effects of two HDAC inhibitors with distinct concomitant DNA hypermethylation or hypomethylation in breast cancer cells

“…Aberrant expression of these HDACs has been identified in many pathological diseases including cancer, diabetes, and neurodegenerative disorders [16]. Several studies have implicated the role of class I and class II HDACs in breast cancer.…”

Znaczenie minimalnej choroby resztkowej w szpiczaku plazmocytowym — Stanowisko Polskiego Konsorcjum Szpiczakowego

“…Poprawa rokowania jest wynikiem intensywnych badań nad patogenezą PCM i mechanizmami oporności na chemioterapię, które umożliwiły opracowanie i wprowadzenie do praktyki klinicznej nowych grup leków, w tym inhibitorów proteasomu, leków immunomodulujących, inhibitorów deacetylaz histonów i przeciwciał monoklonalnych. Złożone mechanizmy działania przeciwnowotworowego tych leków polegają między innymi na regulacji ekspresji genów indukujących apoptozę, hamowaniu https://journals.viamedica.pl/hematologia angiogenezy, zaburzaniu interakcji między komórkami PCM a mikrośrodowiskiem szpiku i stymulowaniu odpowiedzi immunologicznej chorego na komórki szpiczaka [8][9][10][11][12]. komórek plazmatycznych w badaniu szpiku niezależnie od klonalności, brak guzów plasmocytoma w tkankach miękkich [13].…”