Elsevier

Biochemical Pharmacology

Volume 55, Issue 12, 15 June 1998, Pages 1973-1981
Biochemical Pharmacology

Original Articles
Reactive Oxygen Species and Intracellular Ca2, Common Signals for Apoptosis Induced by Gallic Acid

https://doi.org/10.1016/S0006-2952(98)00041-0Get rights and content

Abstract

Gallic acid (3,4,5-trihydroxybenzoic acid), a naturally occurring plant phenol, induces cell death in apparently different manners, depending on cell lines. Flow cytometric analysis and agarose gel electrophoresis indicated that internucleosomal breakdown of chromatin DNA was observed in HL-60RG cells but not in dRLh-84, HeLa, and PLC/PRF/5 cells, and that the action of gallic acid was independent of cell cycle. A detailed study of signal transduction revealed that the gallic acid-induced cell death of all cells tested in this study was prevented by treatment with the intracellular thiol antioxidant N-acetyl-l-cysteine, catalase, and the intracellular calcium chelator bis-(o-aminophenoxy)-N,N,N,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM). However, the effects of ascorbic acid, superoxide dismutase, EGTA, the endonuclease inhibitor zinc sulfate, the calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), and the NADPH oxidase inhibitor diphenyleneiodonium chloride on cell death were different depending on the cell type, suggesting that the death signal induced by gallic acid was diverse among different cell types, although the production of reactive oxygen species, such as H2O2, and the elevation of intracellular calcium concentration were required as common signals.

Section snippets

Materials

Gallic acid (Nakalai Tesque Co.) was recrystallized from hot water and used for the following experiment. Donor BS, FBS, MEM-Eagle’s salts (with nonessential amino acids), and RPMI-1640 were obtained from the Irvine Scientific Co. LAH and antibiotics (penicillin and streptomycin) were from Life Technologies Inc. Trypsin (pancreas protease) was from the Merck Co. BAPTA-AM, SOD, catalase, NAC, verapamil, and DPhl were purchased from Wako Pure Chemical Industries. Proteinase K and RNase A were

Results

We previously reported that gallic acid shows cytotoxic activity against HL-60RG, dRLh-84, HeLa, and PLC/PRF/5 cells with ic50 values of 5.4, 6.2, 6.1, and 6.6 μg/mL, respectively 29, 30, and that the death of HL-60RG cells was by apoptosis, evidenced by internucleosomal DNA fragmentation, cell shrinkage, disappearance of microvilli, chromatin condensation, and apoptotic body formation [30]. In this study, therefore, we examined the death of other types of cells and the signal transduction

Discussion

Diverse factors are known to elicit apoptosis, including hormones, toxins, chemotherapeutic drugs, carcinogens, growth factor withdrawal, and physical trauma. The cellular signaling events leading to apoptosis are also quite varied. They include increased Ca2+ levels, activation of protein kinase C or protein kinase A, activation of tyrosine kinase, the production of ceramide, and caspase activation. In this study, we found that gallic acid induced apoptosis in four kinds of cell lines via

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