Abstract
The principal finding from this study was the recognition that the α-adrenergic antagonist, phenoxybenzamine, possesses histone deacetylase inhibitory activity. Phenoxybenzamine is approved by the United States Food and Drug Administration for the treatment of hypertensive crises associated with tumors of the adrenal medulla, pheochromocytomas. It has several “off label” indications relative to its capacity to relax vascular smooth muscle and smooth muscle of the urogenital tract. The drug also has a long history of apparent efficacy in ameliorating, and perhaps reversing, the severe symptoms of neuropathic pain syndromes. Our interest in this feature of the drug relates to the fact that certain types of neuropathic pain, in particular complex regional pain syndrome, demonstrate a proliferative nature, with the capacity to spread from an injured limb, for example, to a non-injured limb and perhaps to essentially the entire body. Sensory neuronal sprouting in the spinal cord has been observed under conditions where there is a high sensory input from painful stimuli. Searches of gene expression signatures in the BroadBuild02 Molecular Signature Database using their connectivity map software suggested that phenoxybenzamine may have histone deacetylase inhibitory activity. Studies by others have reported inhibitory effects of phenoxybenzamine on growth, invasion and migration of human tumor cell cultures and, in one study, inhibition of tumor expansion in animal experiments. Inhibitory effects on human tumor cell cultures are also reported in the present study. Phenoxybenzamine was also found to have histone deacetylase inhibitory activity; histone deacetylase isoforms 5, 6, and 9 were the most sensitive to inhibition by phenoxybenzamine. The importance of elevated levels of these isoforms as biomarkers of poor prognosis in human malignant disease, and the recognized suppression of tumor growth that may accrue from their inhibition, opens consideration of possible translation of phenoxybenzamine to new clinical applications. This might be facilitated by the fact that phenoxybenzamine is already an approved drug entity. There appears to be no previous report of the activity of phenoxybenzamine as a histone deacetylase inhibitor.
Highlights
Phenoxybenzamine (PBZ) is classified chemically as a haloalkylamine (Fig 1)
The gene enrichment score for PBZ was 0.818, p = 0.00193; it ranked 14th in relation to an enrichment score of 0.974 for MS-275, 0.973 for SAHA, 0.942 for scriptaid, and 0.895 for trichostatin A (TSA), all established HDAC inhibitors (Table 1)
When the “selectivity” option of Connectivity Map (CMap) was used to probe the relation of PBZ to other gene signatures in the Molecular Signature Database (MSigDB), the output produced a considerable list of gene enrichment scores for PBZ that were greater than that presented in relation to the Glaser [19] signature, and gave further evidence of possible association with various involvements in histone modifications (Table 2)
Summary
Phenoxybenzamine (PBZ) is classified chemically as a haloalkylamine (Fig 1) It was approved in 1953 by the United States Food and Drug Administration (FDA) for the treatment of hypertensive emergencies, in particular for the control of blood pressure in patients secreting large quantities of epinephrine and norepinephrine from tumors of the adrenal medulla, termed pheochromocytomas. An initial study was based on the known non-competitive (irreversible) alpha-adrenergic antagonist activity of PBZ against the mediators of the sympathetic nervous system, norepinephrine and epinephrine, in an attempt to antagonize the presumed sympathetic dystrophy [2,3]. Apparent efficacy was observed in this small human study This first study employed an investigational intravenous formulation of PBZ, but further work was precluded by the lack of availability of a stable intravenous formulation; there is still no preparation available today
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