A Focus on Heme Oxygenase-1 (HO-1) Inhibitors

Abstract

The aim of this review is to highlight the advances in the field of heme oxygenase-1 (HO-1) inhibitors over the past years, particularly from a medicinal chemistry point of view; progresses made in the field strongly helped to clarify physiological roles of the heme oxygenase (HO) system. HO is a family of ubiquitously expressed enzymes which regulate the regiospecific catabolism of heme leading to the formation of equimolar amounts of carbon monoxide (CO), ferrous iron (Fe⁺⁺), and biliverdin. HO exists in two distinct, catalytically active isoforms: HO-1 and HO-2. HO-1 is an inducible 32-kDa protein, while HO-2 is a constitutively synthesized 36-kDa protein and generally is unresponsive to any of the inducers of HO-1. A third isoform, HO-3, is still an elusive protein. The HO system, along with its catabolism products, is involved in a variety of crucial physiological functions, including cytoprotection, inflammation, anti-oxidative effects, apoptosis, neuro-modulation, immune-modulation, angiogenesis, and vascular regulation. The use of selective HO inhibitors is a very important tool to clarify the role of the HO system and the mechanisms underlying its physiological effects and pathological involvement; due to the inducible nature of HO-1, selective inhibition of HO-1 isoform is generally preferable. Notably, HO-1 inhibitors may be also beneficial in therapeutic applications and have been mainly studied for treatment of hyperbilirubinemia and certain types of cancer. Historically, the first molecules used as non selective HO-1 inhibitors were metalloporphyrins (Mps). The subsequent development of the imidazole-dioxolane derivatives afforded the first generation of non-porphyrin based, isozyme selective HO-1 inhibitors.

Chemical-induced coordinated and reciprocal changes in heme metabolism, cytochrome P450 synthesis and others in the liver of humans and rodents

“…Our study using metalloporphyrins revealed that although pretreatment with Co-PP inhibits LPS-mediated induction of inducible nitric oxide synthase gene expression, Sn-PP does not have its inhibitory effect, suggesting the importance of HO-1 activity in the inhibition of immunostimulation (Kinobe et al, 2008;Ashino et al, 2008). Pittalà et al (2013) have recently published a review that highlights the historical advances in the field of HO-1 inhibitors, particularly from a medicinal chemistry point of view; the progress made in the field has strongly helped to clarify physiological roles of HO system. They have found that metalloporphyrins are non-selective inhibitors of HO when clinically or experimentally used both in vivo and in vitro.…”

“…HO-1 has been shown to be regulated by complex intracellular signaling cascades. To date, extensive studies have been conducted on the regulation of HO-1 upregulation and so many excellent reviews have been published (Maines et al, 1986;Maines, 1992Maines, , 1997Kikuchi et al, 2005;Prawan et al, 2005;Vlahakis et al, 2006Vlahakis et al, , 2009Pittalà, 2013). Briefly, HO-1 gene expression is mediated by many transcription factors, such as nuclear factor E2-related factor-2 (Nrf2), activator protein-1 (AP-1), and nuclear factor-kappa B (NF-κB), and some of their up-stream kinases, such as mitogen-activated protein kinases, phosphatidylinositol 3-kinase, and protein kinases A and C. The activation of these kinases by chemical electrophiles can directly cause phosphorylation of Nrf2 at serine or threonine residue, and thus lead to the up-regulation of HO-1.…”

Beyond SNPs and CNV: Pharmacogenomics of Polymorphic Tandem Repeats

“…Considering significant interest in potential modulators of HO-1 activity [82][83][84][85][86], detailed analysis of this genetic polymorphism is warranted. It is quite conceivable that genetic variants with different levels of HO-1 expression may change the therapeutic effect of several drug inducers of HO-1 including aspirin, statins, mimetic peptides, probucol, losartan, paclitaxel, rapamycin, cyclosporine [82].…”

Apurinic/Apyrimidinic Endonuclease/Redox Factor-1 (APE1/Ref-1) Redox Function Negatively Regulates NRF2

“…Speculating future translational implications, such combinations may exhibit lower toxicity on (well oxygenated) normal tissues and target in particular tumor cells surviving in hypoxic compartments, which represent important sources of therapeutic failure. We are aware of the limitations of porphyrin-based compounds, however, our investigation was intended to serve as proof of principle, in anticipation of newer generations of HMOX-1 inhibitors such as imidazole-dioxolane derivatives, currently under evaluation (42).…”