Histone Deacetylase Inhibitors: Emerging Mechanisms of Resistance

Abstract

The histone deacetylase inhibitors (HDIs) have shown promise in the treatment of a number of hematologic malignancies, leading to the approval of vorinostat and romidepsin for the treatment of cutaneous T-cell lymphoma and romidepsin for the treatment of peripheral T-cell lymphoma by the U. S. Food and Drug Administration. Despite these promising results, clinical trials with the HDIs in solid tumors have not met with success. Examining mechanisms of resistance to HDIs may lead to strategies that increase their therapeutic potential in solid tumors. However, relatively few examples of drug-selected cell lines exist, and mechanisms of resistance have not been studied in depth. Very few clinical translational studies have evaluated resistance mechanisms. In the current review, we summarize many of the purported mechanisms of action of the HDIs in clinical trials and examine some of the emerging resistance mechanisms.

Synthesis of 1,2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation

“…9,10 Varinostat and romidepsin are the FDA approved HDIs approved for the treatment of cutaneous T cell lymphoma and currently many more HDIs are in clinical trials. 11, 12 Many of these HDIs are reported to induce their anticancer effect by modulating both the acetylation of histones via their primary effects on HDACs, but many of them have also been found to modulate non-histone proteins, including tubulin. 13 Triazole derivatives have been proved to possess various pharmacological properties including antiproliferative, antiretroviral, antimicrobial, anticonvulsant and transforming growth factor β1 type 1 receptor inhibition.…”

Combined autophagy and HDAC inhibition

“…[12][13][14] We previously showed that HDAC inhibitor-induced autophagy significantly blunts its anticancer activity. Accordingly, genetic or pharmacological disruption of autophagy synergistically modulated the pro-apoptotic and cytostatic effects of VOR in models of imatinib-resistant chronic myeloid leukemia and colon cancer.…”

Molecular, biological characterization and drug sensitivity of chidamide‑resistant non‑small cell lung cancer cells

“…The mechanisms of HDACi resistance include the upregulation of P-glycoprotein, other ATP-binding cassette transporters, cell cycle proteins and signaling proteins, alterations to HDAC protein level, increases in thioredoxin level, nuclear factor-κB activation and anti-apoptotic/prosurvival mechanisms (26). The molecular mechanism for acquired resistance varies in different HDACi-resistant cells.…”