Acquired vorinostat resistance shows partial cross-resistance to ‘second-generation’ HDAC inhibitors and correlates with loss of histone acetylation and apoptosis but not with altered HDAC and HAT activities

Abstract

Histone deacetylase (HDAC) inhibitors such as vorinostat (suberoylanilide hydroxamic acid), valproic acid, romidepsin , and LBH589 comprise a relatively new class of potent anticancer agents. This study provides evidence for the potential of vorinostat to cause acquisition of multidrug resistance protein-independent resistance in HCT116 colon tumor cells. This acquired resistance is moderate (two-fold to three-fold), is nonreversible, and correlates with the loss of responses typically seen with HDAC inhibitors, that is the loss of acetylation of the histones H2A, H2B, H3, and H4, the loss of the G2/M checkpoint activation, and the loss of caspase 3-dependent and caspase 7-dependent apoptosis. This acquired resistance also associates with cross-resistance to the hydroxamate-class (LBH589 and JNJ26481585) and to the aliphatic acid-class (valproic acid) HDAC inhibitors but not to the benzamideclass (MGCD0103) and the cyclic peptide-class (romidepsin) HDAC inhibitors. The acquired HDAC inhibitor resistance described hereis not a result of altered HDAC and histone acetyltransferase activities and differs from that previously reported for romidepsin. The present study provides evidence for the potential of vorinostat to cause acquisition of MDRindependent resistance in HCT116 colon tumor cells. This acquired resistance is moderate (2 to 3-fold), is non-reversible, and correlates with the loss of responses typically seen with HDAC inhibitors, i.e. the loss of acetylation of the histones H2A, H2B, H3, and H4, the loss of the G2/M checkpoint activation, and the loss of caspase 3-and caspase 7-dependent apoptosis. This acquired resistance also associates with cross-resistance to the hydroxamate-class (LBH589 and JNJ26481585) and to the aliphatic acid-class (VPA) HDAC inhibitors but not to the benzamideclass (MGCD0103) and the cyclic peptide-class (romidepsin) HDAC inhibitors. The herein described acquired HDAC inhibitor resistance is not due to altered HDAC and HAT activities and differs from that previously reported for romidepsin.

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

“…The molecular mechanism for acquired resistance varies in different HDACi-resistant cells. The acquired resistance of HCT116/VOR cells was associated with a reduction in histone acetylation, G2/M checkpoint activation and apoptosis susceptibility (20). Pan-HDACi-resistant HL-60/LR cells expressed higher levels of HDAC1, 2 and 4, but lacked expression of HDAC6, with concomitant hyper-acetylation of heat shock protein 90 (21).…”

“…A previous study demonstrated that HL-60/LR cells, human acute myeloid leukemia cells resistant to LAQ824 (a hydroxamic acid analog pan-HDACi), exhibited a markedly higher growth compared with parental HL-60 cells (21). A vorinostat-induced subline, HCT116/vorinostat, exhibited a slightly slower growth rate compared with the parental HCT116 cell line (20). The different results indicate that the growth rate of HDACi-resistant cell lines may be drug-specific, cell type-specific or even case-specific.…”

“…A number of HDACi-resistant cancer cell lines have already been reported (20,21,25). 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).…”

“…Acquired resistance to anticancer agents is common in cancer therapy. Previous studies have revealed that the acquired resistance to the HDACi vorinostat is associated with a lack of G2 checkpoint activation and a lack of HDAC6 expression, with an increased level of HDAC1, 2 and 4 expression (20,21). Another HDACi, romidepsin, may cause the reversible induction of multidrug resistance protein expression in tumor cells, leading to transient resistance (22,23).…”

MLH1 protects from resistance acquisition by the histone deacetylase inhibitor trichostatin A in colon tumor cells

“…We have previously shown that suberoylanilide hydroxamic acid (SAHA, vorinostat), a representative of the class of histone deacetylase (HDAC) inhibitors, can cause acquisition of irreversible and multidrug resistance-independent HDAC inhibitor-resistance in HCT116 colon tumor cells, with the corresponding losses of growth inhibition, of apoptosis, and of histone acetylation (1,2). HDAC inhibitors are a class of anticancer agents that act by epigenetically regulating gene expression through chromatin remodeling.…”