Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

Abstract

Background and purpose: Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated antiangiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate. Experimental approach: Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos. Key results: Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser 78 phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H 2 S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity. Conclusions and implication: S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.

Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton

“…Lethality was 100% at 5 μM thiolutin. Similar concentrations of two other dithioles, D3T and ADT, had little toxicity (Isenberg et al 2007). At 1 μM concentration, thiolutin-treated embryos (Fig.…”

“…1b)-treated embryos, with minimal disruption of the trunk vasculature. ADT-treated embryos showed vascular and morphological defects only at a fivefold-higher concentration (Isenberg et al 2007, and data not shown). Vascular defects in thiolutin embryos could not be independently assessed above 1 μM due to lethality, but thiolutin concentrations of 1 μM or less showed dose-dependent circulatory defects at 26 hpf when compared to age-matched DMSO-treated embryos (Fig.…”

“…The expression and/or phosphorylation of Hsp27 can be up-regulated in response to stress stimuli. In endothelial cells, phosphorylation of Hsp27 is a shared response to a number of angiogenesis inhibitors (Keezer et al 2003;Bix et al 2004) including two dithiolethiones that are structurally related to thiolutin (Isenberg et al 2007). Activation of the p38 MAP kinase signaling pathway leads to human Hsp27 phosphorylation at residues S 15 , S…”

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

“…Dithiolethiones and related compounds have previously been explored as inhibitors of carcinogenesis and have shown considerable promise in animal models of edema and gastrointestinal inflammation (extensively reviewed in [114,115]; summarized in Table 2). However, it is possible that some of the observed biological effects associated with ADT-OH derivatives were due to the dithiolethione moiety itself, rather than released H 2 S. Indeed, an examination of the pertinent literature shows that dithiolethiones, including ADT-OH, are reactive with thiols and elicit several effects that may not be due to H 2 S. For example, Isenberg et al [116] and Moody et al [117] recently showed that the dithiolethione moiety of ADT-OH-modified NSAIDs and valproate rather than released H 2 S inhibited angiogenesis and cell proliferation. Others have shown dithiolethiones to induce the synthesis of phase II enzymes (e.g., glutathione-S-transferase, NAD[P]H, quinone oxidoreductase), GSH reductase and catalase [118][119][120][121][122].…”

GYY4137, a Novel Water-Soluble, H2S-Releasing Molecule

“…Many of these have been designed with the specific intent of delivering controlled levels of H 2 S gas to tissues. Of particular interest are a number of structurally divergent molecule classes encompassing H 2 S releasing nonsteroidal antiinflammatory drugs (Isenberg et al, 2007;Sparatore et al, 2009), L-cysteine activated arylthioamide H 2 S donor molecules (Martelli et al, 2013), caged gem-dithiol derivatives that release H 2 S upon light stimulation (DevarieBaez et al, 2013) and molecules that release H 2 S in aqueous systems. Many of these compounds, that are now available commercially, have been reviewed elsewhere (Kashfi & Olson, 2013;Song et al, 2014).…”