A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-α Production in Murine Macrophages

Abstract

Cisplatin has been used for the treatment of various solid cancers or sarcomas; however, it can induce severe adverse effects. Among these adverse effects, nephrotoxicity, which has the potential to be a dose-limiting factor of this agent, develops due to the secretion of tumor necrosis factor-α (TNF-α) from macrophages; however, the precise mechanisms are still unclear. To elucidate possible mechanisms, we investigated the involvement of mitogen-activated protein kinases (MAPK) and reactive oxygen species (ROS) in cisplatin-induced TNF-α mRNA expression and protein production in the mouse macrophage-like cell line, RAW 264. Cisplatin (1 μM) significantly increased TNF-α mRNA expression and protein production. Extracellular-regulated kinase (ERK) and p38 MAPK, but not c-Jun N-terminal kinase (JNK), phosphorylation increased in response to cisplatin. Although an ERK inhibitor (PD98059) suppressed both cisplatin-induced TNF-α mRNA expression and its protein production, a p38 MAPK inhibitor (SB203580) decreased TNF-α protein production only. A JNK inhibitor (SP600125) had no effect on cisplatin-induced TNF-α mRNA expression. Furthermore, a scavenger of ROS, N,N'-dimethylthiourea, suppressed both ERK activation and TNF-α mRNA expression. These results suggest that the phosphorylation of ERK by ROS is involved in cisplatin-induced TNF-α mRNA expression and that the signaling pathway of p38 MAPK is related to TNF-α protein production.

The Protective Role of N,N’-Dimethylthiourea and Its Effect on Hydrogen Peroxide Level of Hela Kyoto Cells under Cisplatin Action

“…Since the addition of DMTU resulted in a significant decrease in the percentage of dead cells and did not increase the percentage of early apoptotic cells, we can deduce that DMTU plays the protective role for cells treated with cisplatin. The results are consistent with works of other researches showing the ability of DMTU to reduce the accumulation of singlet oxygen, hydroxyl radical [17], H 2 O 2 [18], and block the activation of p53, leading to weakening of p53 upregulated modulator of apoptosis alpha (PUMA-α) production and suppression of the mitochondrial pathway of apoptosis during cisplatin treatment [16,21].…”

“…For this purpose, in this study, we employed ROS scavenger N,N'-dimethylthiourea (DMTU). DMTU is a highly efficient absorber of OH • , 1 O 2 [16,17], and H 2 O 2 [18], known to decrease the H 2 O 2 -induced damage of cultured endothelial cells [19], to reduce the cisplatin-induced tumor necrosis factor-alpha (TNF-α) expression in macrophages in vitro, and to prevent the development of oxidative stress, activation of p53 and, as a consequence, apoptosis of renal and hepatic cells in vivo [20][21][22][23]. An important step is to carry out experiments on cytotoxicity of cisplatin under conditions of hydrogen peroxide removal from cells using DMTU.…”

S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNFα/TNFR1-Mediated Cell Survival to Cell Death

“…Previous studies showed that TNFa expression and secretion from macrophage and head and neck squamous cell cancer can be induced by cisplatin (16,17). Altogether, our observations suggest that platinum derivative chemotherapy could increase TNFa production levels in the tumor microenvironment and inflammation, and might sustain tumor development and/or progression.…”

“…Previous studies have shown that TNFa expression and secretion from macrophage and some cancer cell lines can be induced by platinum derivative (cisplatin; refs. 16,17). OXA plus 5-fluorouracil (5-FU) and folinic acid (referred to as Folfox) or IRI plus 5-FU and folinic acid (referred to as Folfiri) are the standard treatments used to treat advanced colon cancer but also other types of cancer.…”

Effects of inflammatory factors including plasma tumor necrosis factor-α in the clinical treatment of acute respiratory distress syndrome

“…TNF-α, secreted by activated neutrophile granulocytes and mononuclear macrophages, is a multi-functional polypeptide (6). It may stimulate inflammatory cells and produce toxic effects when associated with corresponding receptors; tissues eventually become severely damaged due to the increase in inflammatory factors, including IL-6 and IL-8 (7).…”