Cadmium-induced Apoptosis in Murine Macrophages is Antagonized by Antioxidants and Caspase Inhibitors
- 1 June 2006
- journal article
- research article
- Published by Informa UK Limited in Journal of Toxicology and Environmental Health, Part A
- Vol. 69 (12), 1181-1201
- https://doi.org/10.1080/15287390600631144
Abstract
Cadmium is a toxic heavy metal that accumulates in the environment and is commonly found in cigarette smoke and industrial effluents. This study was designed to determine the role of reactive oxygen species (ROS) generation, and its antagonism by antioxidants, in cadmium-mediated cell signaling and apoptosis in murine macrophage cultures. Cadmium-generated ROS production was observed in J774A.1 cells at 6 h, reverting to control levels at 16 and 24 h. The ROS production was concentration related between 20 and 500 μM cadmium. Activation of caspase-3 was observed at 8 h and DNA fragmentation at 16 h in the presence of 20 μM cadmium, suggesting that caspase-3 activation is a prior step to DNA fragmentation in cadmium-induced apoptosis. Inhibitors of caspase-3, -8, -9, and a general caspase inhibitor suppressed cadmium-induced caspase-3 activation and apoptosis indicating the importance of caspase-3 in cadmium-induced toxicity in these cells. Protection against the oxidative stress with N-acetylcysteine (NAC) and silymarin (an antioxidant flavonoid) blocked cadmium-induced apoptosis. Pretreatment of cells with NAC and silymarin prevented cadmium-induced cell injury, including growth arrest, mitochondrial impairment, and necrosis, and reduced the cadmium-elevated intracellular calcium ([Ca2+]i), suggesting that the oxidative stress is a source of increased [Ca2+]i. NAC inhibited cadmium-induced activation of mitogen-activated protein kinases, the c-Jun NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK). However, silymarin provided only a partial protection for JNK activation, and only at the low concentration did it inhibit cadmium-induced ERK activation. Inhibition of caspase-3 protected oxidative stress produced by cadmium, suggesting that the activation of caspase-3 also contributes to generation of reactive oxygen species (ROS). Results emphasized the role of ROS, Ca2+ and mitogen-activated protein kinases in cadmium-induced cytotoxicity in murine macrophages.Keywords
This publication has 45 references indexed in Scilit:
- Apoptosis signaling triggered by the marine alkaloid ascididemin is routed via caspase-2 and JNK to mitochondriaOncogene, 2003
- SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinaseProceedings of the National Academy of Sciences, 2001
- Hydrogen peroxide induces apoptosis of chondrocytes; involvement of calcium ion and extracellular signal-regulated protein kinaseInflammation Research, 2001
- Activation of JNK, p38 and ERK mitogen-activated protein kinases by chromium(VI) is mediated through oxidative stress but does not affect cytotoxicityCarcinogenesis: Integrative Cancer Research, 2000
- Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmiumCarcinogenesis: Integrative Cancer Research, 2000
- Cadmium Induces c-myc, p53, and c-jun Expression in Normal Human Prostate Epithelial Cells as a Prelude to ApoptosisToxicology and Applied Pharmacology, 2000
- Apoptosis: checkpoint at the mitochondrial frontierMutation Research/DNA Repair, 1999
- Cadmium, Gene Regulation, and Cellular Signalling in Mammalian CellsToxicology and Applied Pharmacology, 1997
- INDUCTION OF c-mycAND c-junPROTO-ONCOGENE EXPRESSION IN RAT L6 MYOBLASTS BY CADMIUM IS INHIBITED BY ZINC PREINDUCTION OF THE METALLOTHIONEIN GENEJournal of Toxicology and Environmental Health, 1996
- Mitochondrial regulation of superoxide by Ca2+: An alternate mechanism for the cardiotoxicity of doxorubicinToxicology and Applied Pharmacology, 1991