In vivo anti‐myeloma activity and modulation of gene expression profile induced by valproic acid, a histone deacetylase inhibitor

Abstract

Summary Valproic acid (VPA) is a well‐tolerated anticonvulsant that exerts anti‐tumour activity as a histone deacetylase inhibitor. This study investigated the in vitro and in vivo activity of VPA against multiple myeloma (MM) cells. In vitro exposure of interleukin‐6‐dependent or ‐independent MM cells to VPA inhibited cell proliferation in a time‐ and dose‐dependent manner and induced apoptosis. In a cohort of severe combined immunodeficiency mice bearing human MM xenografts, VPA induced tumour growth inhibition and survival advantage in treated animals versus controls. Flow cytometric analysis performed on MM cells from excised tumours showed increase of G0–G1 and a decreased G2/M‐ and S‐phase following VPA treatment, indicating in vivo effects of VPA on cell cycle regulation. Gene expression profiling of MM cells exposed to VPA showed downregulation of genes involved in cell cycle progression, DNA replication and transcription, as well as upregulation of genes implicated in apoptosis and chemokine pathways. Pathfinder analysis of gene array data identified cell growth, cell cycle, cell death, as well as DNA replication and repair as the most important signalling networks modulated by VPA. Taken together, our data provide the preclinical rationale for VPA clinical evaluation as a single agent or in combination, to improve patient outcome in MM.

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

“…In vitro exposure of interleukin-6-dependent or -independent MM cells to VPA inhibits cell proliferation in a time-and dose-dependent manner and induces apoptosis (20). In a cohort of severe combined immunodeficienct mice bearing human MM xenografts, VPA was observed to induce tumor growth inhibition and improve survival rates in treated animals compared with controls (20). ATO has long been used as a therapeutic agent.…”

Pleiotropic anti-myeloma activity of ITF2357: inhibition of interleukin-6 receptor signaling and repression of miR-19a and miR-19b

“…12 Although a genome-wide comparison is not possible, the gene pattern modulated by ITF2357 is in line with that previously observed in MM1 cells treated with other HDAC K. Todoerti et al 266 haematologica | 2010; 95(2) inhibitors. 29,30 Indeed several genes shown here, such as CD138, CD126, IGF1, TNFRSF1, MYB, CDK3, CDK1B, CDK1A (p21), CDKN1C (p57), CDKN2D (p19) and APAF1, have been previously identified to be modulated in MM cells by the pan-HDAC inhibitor SAHA. 29 Interestingly, CDK1A, CDKN1C, CDKN1B (p27), MYC, BID and CD138 have also been described to be modulated in MM cells by the class I specific HDAC inhibitor valproic acid.…”

“…29 Interestingly, CDK1A, CDKN1C, CDKN1B (p27), MYC, BID and CD138 have also been described to be modulated in MM cells by the class I specific HDAC inhibitor valproic acid. 30 A full understanding of the role of the various HDAC isoforms in regulating specific sets of genes does, however, await further analyses with isoform-specific inhibitors using identical cellular targets and time points.…”

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

“…This is in line with other studies, demonstrating that upregulation of p21 Waf1 is a hallmark for the HDACi-induced cell cycle arrest. 25,26,28,[43][44][45] This corresponds with the anti-proliferative activity of JNJ-26481585. However at 72 h incubation, cell cycle arrest is lost, most likely because of the large increase of apoptotic cells.…”