Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury†

Abstract

The nuclear protein high mobility group box 1 (HMGB1) is an important inflammatory mediator involved in the pathogenesis of liver ischemia/reperfusion (I/R) injury. Strategies aimed at preventing its release from stressed or damaged cells may be beneficial in preventing inflammation after I/R. Cisplatin is a member of the platinating chemotherapeutic agents and can induce DNA lesions that are capable of retaining high mobility group proteins inside the nucleus of cells. In vitro studies in primary cultured rat hepatocytes show that nontoxic concentrations of cisplatin can sequester HMGB1 inside the nucleus of hypoxic cells. Similarly, the in vivo administration of nontoxic doses of cisplatin prevents liver damage associated with a well-established murine model of hepatic I/R as measured by lower circulating serum aminotransferase levels, lower hepatic inflammatory cytokine levels including tumor necrosis factor ␣ and interleukin-6, lower inducible NO synthase expression, and fewer I/R-associated histopathologic changes. The mechanism of action in vivo appears to involve the capacity of cisplatin to prevent the I/R-induced release of HMGB1 as well as to alter cell survival and stress signaling in the form of autophagy and mitogen-activated protein kinase activation, respectively. Conclusion: Low, nontoxic doses of cisplatin can sequester HMGB1 inside the nucleus of redox-stressed hepatocytes in vitro and prevent its release in vivo in a murine model of hepatic I/R. Furthermore, cell survival and stress signaling pathways are altered by low-dose cisplatin. Therefore, platinating agents may provide a novel approach to mitigating the deleterious effects of I/R-mediated disease processes. (HEPATOLOGY 2009;50:565-574.)

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

“…(2013) 61:43-58 45 (PARP-1)-mediated cell death. More importantly, the antinecrosis function of autophagy has important biological functions in various pathological processes and diseases, including cancer and ischemia/reperfusion injury (Cardinal et al 2009;Esposti et al 2010). ''Autophagic cell death'' is morphologically defined as a type of cell death that occurs in the absence of chromatin condensation but accompanied by massive autophagic vacuolization of the cytoplasm (Yu et al 2004a(Yu et al , 2004b.…”

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

“…Recent studies show that Bβ15-42 (the fibrin-derived peptide), PNU-282987 (a selective α7 nicotinic acetylcholine receptor agonist), EPC-K1 (the vitamin E derivative), melatonin, cisplatin and glycyrrhizin attenuate warm liver I/R damage partly through inhibition of HMGB1 release (47)(48)(49)(50)(51)(52). Interestingly, pretreatment of mice with HMGB1 protein significantly decreased liver I/R injury through upregulation of IL-1R-associated kinase-M, a negative regulator of TLR4 signaling (53).…”

Low dosages: new chemotherapeutic weapons on the battlefield of immune-related disease

“…The in vivo administration of non-toxic doses of Cis prevented liver damage in a murine model of hepatic ischemia/ reperfusion, resulting in decreased levels of inflammatory cytokines, such as tumor-necrosis factor-a, IL-6 and inducible NO synthase, inhibition of mitogen-activated protein kinase activation, autophagy and ischemia/reperfusion-associated histopathological changes. 64 Together, these findings suggest that the mechanism for the antiinflammatory and therapeutic effects of low-dose Cis in non-cancer diseases may occur via its regulation of HMGB1 release as well as its ability to alter cell survival and stress signaling in the form of autophagy and mitogen-activated protein kinase activation. Currently, the activities of HMGB1 are a focus of attention for the study of the induction and propagation of autoimmune conditions.…”

“…In addition, low-dose Cis was also reported to sequester HMGB1 inside the nucleus of redoxstressed hepatocytes. 64 Therefore, it is assumed that targeting HMGB1 might be a mechanism involved in the therapeutic effects of low-dose Cis.…”