Ethyl pyruvate induces necrosis-to-apoptosis switch and inhibits high mobility group box protein 1 release in A549 lung adenocarcinoma cells

Abstract

Ethyl pyruvate (EP), a stable lipophilic pyruvate derivative, has been shown to exert anti-inflammatory activities through inhibiting the expression of various pro-inflammatory mediators as well as circulating levels of high mobility group box protein 1 (HMGB1) in a variety of in vitro and in vivo model systems. Necrotic cell death triggers an inflammatory response through release of HMGB1 in the extracellular space due to the membrane rupture. In an effort to better understand the pharmacological action mechanism that could explain the anti-inflammatory properties of EP, we examined the effects of EP on necrotic cell death in A549 lung adenocarcinoma cells in response to glucose deprivation (GD), a common characteristic of the tumor microenvironment. Here we show that EP prevented GD-induced necrosis and HMGB1 release and switched the cell death mode to apoptosis through inhibiting GD-induced CuZn superoxide dismutase release and ROS production. These results suggest that the necrosisto-apoptosis switch activity of EP may contribute to its anti-inflammatory action and that EP may suppress tumor development possibly through its activity to induce the cell death mode switch from tumor promoting necrotic cell death to tumor suppressive apoptotic cell death.

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

“…50,51 For instance, excess ROS could trigger necrosis in response to metabolic stress and alleviation of ROS production by antioxidants switches the death mode from necrosis to apoptosis. 52,53 In addition, the superoxide generator menadione prevents apoptosis by inactivation of caspases, thus leading to necrosis in HepG2 cells. 54 We observed that oxaliplatin gradually increased ROS level and UDCA could suppress ROS production.…”

Antimicrobial cathelicidin peptide CAP11 suppresses HMGB1 release from lipopolysaccharide-stimulated mononuclear phagocytes via the prevention of necrotic cell death

“…However, in their experiments LDH (a necrotic marker) was also extracellularly released under the stimulation conditions, and the release was correlated with HMGB1 release. Moreover, Lim et al reported that ethyl pyruvate, a stable pyruvate derivative, suppresses the glucose deprivation-induced HMGB1 release from A549 lung adenocarcinoma cells by preventing necrotic cell death and switching cell death mode to apoptosis (23). In addition, Scaffidi et al revealed using HeLa cells that HMGB1 is extracellularly released from necrotic but not apoptotic cells after treatment with various cytotoxic substances (21).…”

“…It has been previously reported that HMGB1 is extracellularly released from various types of cells accompanied with cell death (18,(21)(22)(23). Thus, we determined whether LPSstimulation also induces apoptotic and/or necrotic cell death in RAW264.7 cells.…”

“…Of interest, CAP11 can suppress the elevation of serum HMGB1 level in mouse endotoxin shock model and protect mice from endotoxin lethality (16,17). Moreover, HMGB1 is reported to be extracellularly released, accompanied with cell death (18,(21)(22)(23). Thus, to clarify the inhibitory mechanism of CAP11 on HMGB1 release, we evaluated the effect of CAP11 on the LPS-induced HMGB1 release and apoptotic/necrotic cell death using a murine macrophage cell line RAW264.7 as a target cell.…”

A New Therapeutic Target for Treatment of Cancer: High Mobility Group Box 1 Protein

“…Tümör enjeksiyonundan sonra yükselen serum IL6 ve HMGB1 seviyeleri EP tedavisi alan hayvanlarda belirgin olarak azalır [20]. EP A549 akciğer adenokarsinom hücrelerinde nekroz-apopitoz değişimini uyarır ve HMGB1 salınımını inhibe eder [21].…”