Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate

Abstract

Summary A series of hydroxamates, which are not metalloprotease inhibitors, have been found to be selectively toxic to a range of transformed and human tumour cells without killing normal cells (fibroblasts, melanocytes) at the same concentrations. Within 24 h of treatment, drug action is characterized by morphological reversion of tumour cells to a more normal phenotype (dendritic morphology), and rapid and reversible acetylation of histone H4 in both tumour and normal cells. Two hydroxamates inhibited growth of xenografts of human melanoma cells in nude mice; resistance did not develop in vivo or in vitro. A third hydroxamate, trichostatin A, was active in vitro but became inactivated and had no anti-tumour activity in vivo. Development of dendritic morphology was found to be dependent upon phosphatase activity, RNA and protein synthesis. Proliferating hybrid clones of sensitive and resistant cells remained sensitive to ABHA, indicating a dominant-negative mechanism of sensitivity. Histone H4 hyperacetylation suggests that these agents act at the chromatin level. This work may lead to new drugs that are potent, and selective anti-tumour agents with low toxicity to normal cells.

The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Induces Apoptosis via Induction of 15-Lipoxygenase-1 in Colorectal Cancer Cells

“…Suberoylanilide hydroxamic acid is in phase I and II clinical trials for the treatment of various cancers and has shown anticancer activity at doses that are well tolerated by patients (11,12). These preclinical results and the clinical trials show that suberoylanilide hydroxamic acid targets transformed cells in preference to normal cells (9).…”

Histone deacetylase inhibitors specifically kill nonproliferating tumour cells

“…Here, we have demonstrated that HDIs are cytotoxic to both proliferating and nonproliferating cells, with little loss of potency although there is a delay in the onset of cell death. We have previously demonstrated that HDIs have tumour-selective cytotoxicity (Qiu et al, 2000;Qiu et al, 1999). Thus, this class of drugs has many of the characteristics desired in an anticancer drug, selective cytotoxicity and the ability to kill both actively proliferating and nonproliferating tumour cells.…”

Radiosensitization of glioblastoma cells using a histone deacetylase inhibitor (SAHA) comparing carbon ions with X-rays

“…Interestingly, SAHA induces apoptosis in some cancer cells, but not in equivalent normal cells, when combined with either X-rays or carbon ions. It has been postulated that this unexpected finding is related to differing transcriptional regulation between cancer and normal cells (Qiu et al 1999;Minucci and Pelicci 2006). In particular the cyclin-dependent kinase inhibitor 1 gene (p21 WAF1 ), which in general prevents proliferation, is suppressed in many tumour cells but is upregulated by SAHA resulting in cell death (Gui et al 2004).…”