Chlorhexidine-induced apoptosis or necrosis in L929 fibroblasts: A role for endoplasmic reticulum stress.
Chlorhexidine (CHX), widely used as antiseptic and therapeutic agent in medicine and dentistry, has a toxic effect both in vivo and in vitro. The intrinsic mechanism underlying CHX-induced cytotoxicity in eukaryotic cells is, however, still unknown. A recent study from our laboratory has suggested that CHX may induce death in cultured L929 fibroblasts via endoplasmic reticulum (ER) stress. This hypothesis was further tested by means of light and electron microscopy, quantification of apoptosis and necrosis by flow cytometry, fluorescence visualization of the cytoskeleton and endoplasmic reticulum, and evaluation of the expression of 78-kDa glucose-regulated protein 78 (Grp78), a marker of activation of the unfolded protein response (UPR) in cultured L929 fibroblasts. Our finding showing increased Grp 78 expression in CHX-treated cells and the results of flow cytometry, cytoskeleton and endoplasmic reticulum fluorescence visualization, and scanning and transmission electron microscopy allowed us to suggest that CHX elicits accumulation of proteins in the endoplasmic reticulum, which causes ER overload, resulting in ER stress and cell death either by necrosis or apoptosis. It must be pointed out, however, that this does not necessarily mean that ER stress is the only way that CHX kills L929 fibroblasts, but rather that ER stress is an important target or indicator of cell death induced by this drug.
Faria
Gisele
G
Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Cardoso
Cristina R B
CR
Larson
Roy E
RE
Silva
João S
JS
Rossi
Marcos A
MA
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002710:Chlorhexidine / Q000633:toxicity*; D004202:Disinfectants / Q000633:toxicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology*; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008855:Microscopy, Electron, Scanning; D018832:Molecular Chaperones / Q000378:metabolism; D009336:Necrosis / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D014404:Tubulin / Q000378:metabolism
D000199:Actins; D004202:Disinfectants; D000091342:Endoplasmic Reticulum Chaperone BiP; D005456:Fluorescent Dyes; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; D002710:Chlorhexidine