Enhancing the anti-angiogenic action of histone deacetylase inhibitors

Abstract

BackgroundHistone deacetylase inhibitors (HDACIs) have many effects on cancer cells, such as growth inhibition, induction of cell death, differentiation, and anti-angiogenesis, all with a wide therapeutic index. However, clinical trials demonstrate that HDACIs are more likely to be effective when used in combination with other anticancer agents. Moreover, the molecular basis for the anti-cancer action of HDACIs is still unknown. In this study, we compared different combinations of HDACIs and anti-cancer agents with anti-angiogenic effects, and analysed their mechanism of action.ResultsTrichostatin A (TSA) and α-interferon (IFNα) were the most effective combination across a range of different cancer cell lines, while normal non-malignant cells did not respond in the same manner to the combination therapy. There was a close correlation between absence of basal p21WAF1 expression and response to TSA and IFNα treatment. Moreover, inhibition of p21WAF1 expression in a p21WAF1-expressing breast cancer cell line by a specific siRNA increased the cytotoxic effects of TSA and IFNα. In vitro assays of endothelial cell function showed that TSA and IFNα decreased endothelial cell migration, invasion, and capillary tubule formation, without affecting endothelial cell viability. TSA and IFNα co-operatively inhibited gene expression of some pro-angiogenic factors: vascular endothelial growth factor, hypoxia-inducible factor 1α and matrix metalloproteinase 9, in neuroblastoma cells under hypoxic conditions. Combination TSA and IFNα therapy markedly reduced tumour angiogenesis in neuroblastoma-bearing transgenic mice.ConclusionOur results indicate that combination TSA and IFNα therapy has potent co-operative cytotoxic and anti-angiogenic activity. High basal p21WAF1 expression appears to be acting as a resistance factor to the combination therapy.

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

“…As some HDAC inhibitors have the ability to reduce VEGF production, one of the most prominent angiogenic factors in MM, it is possible that JNJ-26481585 not only reduces the MVD through the inhibition of the tumor burden, but also by reducing the VEGF secretion from the MM cells as well as the stromal cells. 43,55,[62][63][64][65] On the other hand, JNJ-26481585 might also affect MVD directly as several HDAC inhibitors, such as valproic acid, trichostatin, NVP-LAQ824 and LBH589, have shown anti-angiogenic properties in vitro and in vivo by affecting endothelial cell survival and function directly. Several in vitro assays showed that HDACi inhibit endothelial cell proliferation, induce cell cycle arrest and inhibit endothelial cell function by decreasing endothelial cell migration, invasion and tube formation.…”

Efficient cell migration requires global chromatin condensation

“…Previously, it has been shown that inhibition of HDACs (Hellebrekers et al, 2006;Kuljaca et al, 2007;Whetstine et al, 2005), as well as inhibition of DNA methylation (Rahnama et al, 2006;Shafiei et al, 2008), interferes with cell migration and invasion. These drugs are used in clinical trials as potential anticancer treatments (Glaser, 2007;Liu et al, 2006;Yoo and Jones, 2006).…”

Targeting Histone Deacetylases for the Treatment of Immune, Endocrine & Metabolic Disorders

“…HDACi have also been shown sensitize breast cancer cells to various other chemotherapy agents including trastuzumab, taxotere, gemcitabine, doxorubicin , docetaxel and epothilone B [122][123][124], while the HDACi LAQ824 has been shown to have a greater antitumour activity in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 in breast cancer cells [125]. The cyclindependent kinase inhibitor flavopiridol has been shown to significantly enhance the ability of Zolinza (SAHA/Vorinostat) to induce cell death in breast cancer cell lines partly through the inhibition of AKT and ERK1/2 activity [126] Induction of apoptosis in breast cancer cells was synergised following cotreatment of the cells with both HDACi and TRAIL [127,128], while a combination of alpha-interferon and trichostatin A was shown to have potent cooperative cytotoxic and anti-angiogenic activity in breast cancer cells [129].…”