Induction of Polyploidy by Histone Deacetylase Inhibitor: A Pathway for Antitumor Effects

Abstract

Histone deacetylase (HDAC) inhibitors can induce various transformed cells to undergo growth arrest and/or death. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor which is in phase I/II clinical trials and has shown antitumor activity in hematologic and solid tumors at doses well tolerated by patients. HDAC is the target for SAHA, but the mechanisms of the consequent induced death of transformed cells are not completely understood. In this study, we report that SAHA induced polyploidy in human colon cancer cell line HCT116 and human breast cancer cell lines, MCF-7, MDA-MB-231, and MBA-MD-468, but not in normal human embryonic fibroblast SW-38 and normal mouse embryonic fibroblasts. The polyploid cells lost the capacity for proliferation and committed to senescence. The induction of polyploidy was more marked in HCT116 p21 WAF1 À/À or HCT116 p53À/À cells than in wild-type HCT116. The development of senescence of SAHA-induced polyploidy cells was similar in all colon cell lines. The present findings indicate that the HDAC inhibitor could exert antitumor effects by inducing polyploidy, and this effect is more marked in transformed cells with nonfunctioning p21 WAF1 or p53 genes. (Cancer Res 2005; 65(17): 7832-9)

Histone deacetylase inhibitors: molecular mechanisms of action

“…G 1 and G 2 arrests are largely associated with induction of p21, which inhibits CDKs regulating G 1 progression (CDK4/6) and G 1 /S transition (CDK2), the activity of proliferating cell nuclear antigen that is required for DNA replication (Vidal and Koff, 2000), and cdc2/CDK1 that regulates G 2 /M transition. Loss of p21 abolishes HDACi-induced G 1 arrest (Archer et al, 1998;Rosato et al, 2001;Xu et al, 2005). G 1 arrest was observed in cells without p21 (Hitomi et al, 2003).…”

“…Normal cells are relatively resistant to HDACi-induced cell death (Burgess et al, 2004;Insinga et al, 2005;Ungerstedt et al, 2005). The cell death pathways identified in mediating HDACiinduced transformed cell death include apoptosis (Rosato and Grant, 2005;Bolden et al, 2006;Minucci and Pelicci, 2006) by the intrinsic (Ruefli et al, 2001) and extrinsic pathways, mitotic catastrophe/cell death (Qiu et al, 2000;Dowling et al, 2005;Xu et al, 2005), autophagic cell death (Shao et al, 2004), senescence and reactive oxygen species (ROS)-facilitated cell death (Rosato and Grant, 2005;Ungerstedt et al, 2005). The response to HDACi appears to depend, in part at least, on the nature of HDACi, concentration and time of exposure, and importantly, the cell context.…”

“…Histone acetylation interferes with histone phosphorylation and disrupts the function of mitotic spindle checkpoint proteins, such as BubR1, hBUB1, CENP-F and CENP-E (Dowling et al, 2005;Robbins et al, 2005). As a result, the cells show a transient arrest at prometaphase, followed with aberrant mitosis such as missegregation and loss of chromosomes, resulting in cell death by either apoptosis or, mitotic cell death/ catastrophe (Qiu et al, 2000;Cimini et al, 2003;Xu et al, 2005). HDACi-induced a-tubulin acetylation does not affect mitosis, although a-tubulin is a component of mitotic spindle that mediates mitosis.…”

Histone Deacetylase Inhibitors for Cancer Therapy

“…In particular, hydroxamic-based HDACIs, such as ABHA, SAHA and SK-7068, induced tumor-selective mitotic defects while normal cells remained unaffected. 14,103,104,110 Lastly, several chimeric oncoproteins characteristic of cancer cells are selectively targeted by HDACIs. HDACIs specifically inhibit PML-RARα in PML cells, resulting in re-expression of RARα responsive genes.…”

“…[1][2][3][4][5][6][7][8] In addition, HDACIs have the advantage of being less toxic in normal cells than in cancer cells. [10][11][12][13][14] Based on their pleiotropic cellular effects and their tumor-selectivity, several HDACIs are currently undergoing clinical trials, and some of them have shown promising anti-tumor activity. [15][16][17][18][19][20][21] While it is clear that HDACIs directly modulate gene transcription by histone hyperacetylation, the molecular underpinnings of their cytotoxicity and tumor-selectivity remain poorly understood.…”