Oxidative stress, a result of an overproduction and accumulation of free radicals, is the leading cause of several degenerative diseases such as cancer, atherosclerosis, cardiovascular diseases, ageing and inflammatory diseases. Polyphenols form an important class of naturally occurring antioxidants, having innumerable biological activities such as anticancer, antifungal, antibacterial, antiviral, antiulcer and anticholesterol, to name a few. Among various polyphenols, gallic acid (3,4,5-trihydroxybenzoic acid), a naturally occurring low molecular weight triphenolic compound, has emerged as a strong antioxidant and an efficient apoptosis inducing agent. Starting from the bioavailability and the biosynthetic pathway of gallic acid, this review includes various in vitro, in vivo and in silico studies providing the mode of action, radical scavenging activity, ability to inhibit lipid peroxidation, maintenance of endogenous defense systems and metal ion chelation by this triphenolic molecule, along with a comprehensive overview of factors responsible for its high antioxidant activity. Gallic acid derivatives have also been found in a number of phytomedicines with diverse biological and pharmacological activities, including radical scavenging, interfering with the cell signaling pathways and apoptosis of cancer cells. The diverse range of applications of this simple polyphenol is due to a fine amalgam between its antioxidant and prooxidant potential. The existing literature on this dual behavior of gallic acid and its derivatives is reviewed here. This is followed by an account of their potential clinical and industrial applications.

Gallic acid: a versatile antioxidant with promising therapeutic and industrial applications

Phenolic antioxidants are ranked by reducing strength and characterized for reversibility using cyclic voltammetry at a glassy carbon electrode. Phenolics with an ortho-diphenol group show a first oxidation peak close to 400 mV (vs. Ag/AgCl) in a model wine solution (12% ethanol, 0.033 M tartaric acid, adjusted to pH 3.6), with a linear concentration dependence below 0.01 mM. Dilution of white wines 10×, and red wines 400×, gave first oxidation peak currents in the 1.5 to 2.2 μA range and 1.9 to 3.4 μC of charge passed by 500 mV, producing values for the concentrations of phenolic antioxidants with low oxidation potentials in the wines. Further peaks in the cyclic voltammograms of the diluted wines correspond to classes of phenolics with higher oxidation potentials, providing a qualitative assessment of wine phenolics based on reducing strength. Keywords: Cyclic voltammetry; wine; phenolics; antioxidants

A cyclic voltammetry method suitable for characterizing antioxidant properties of wine and wine phenolics.

Phenolic acid derivatives with potential anticancer properties--a structure-activity relationship study. Part 1: methyl, propyl and octyl esters of caffeic and gallic acids.

Antioxidant activity of Agaricus sp. mushrooms by chemical, biochemical and electrochemical assays

This review summarises current knowledge on the various molecular chemopreventive or therapeutic mechanisms that may be involved when the administration of flavonoids or polyphenols prevented chemical carcinogenesis in animal models. These mechanisms can be subdivided into the following: 1) the molecular mechanisms involved in preventing carcinogen metabolic activation, 2) the molecular mechanisms for preventing tumour cell proliferation by inactivation or downregulation of prooxidant enzymes or signal transduction enzymes, 3) the molecular cell death mechanisms for the induction of tumour cell death (apoptosis) and the molecular mechanisms for the inhibition of isolated mitochondria functions. Many of the flavonoids and polyphenols found in diets, supplements or herbal medicine were also ranked using "accelerated cytotoxic mechanism screening" by a combinatorial approach utilising isolated rat hepatocytes. A strong correlation of an early collapse of the mitochondrial membrane potential and cell death was found for most of the cytotoxic polyphenols but did not occur with non-toxic polyphenols. This screening could prove useful for eliminating polyphenols that have the potential for adverse health effects and for selecting safe and effective polyphenolic candidates for further development as supplements for preventing cancer or cardiovascular disease. Safety concerns of flavonoid/polyphenol supplements are also reviewed.

Cancer chemoprevention and apoptosis mechanisms induced by dietary polyphenolics.

Antioxidant activity of gallates: an electrochemical study in aqueous media

Inhibition of tumoral cell respiration and growth by nordihydroguaiaretic acid.

Alkyl esters of gallic acid inhibited the respiration rate of mouse sarcoma 786A and mouse mammary adenocarcinoma TA3 cell lines and its multiresistant variant TA3-MTX-R more effectively than gallic acid, both in the absence and in the presence of the uncoupler CCCP. The order of inhibition of the respiration rate by gallates in intact cells was n-octyl- approximately iso-amyl- approximately n-amyl- approximately iso-butyl->n-butyl->iso-propyl->n-propyl-gallate>>gallic acid. Sarcoma 786A was significantly more susceptible to all seven esters than the TA3 cell line. Respiration rates of the TA3-MTX-R cell line showed almost the same sensitivity to these esters as the TA3 cell line. However, hepatocytes were significantly less sensitive than all tumor cells tested. These alkyl gallates blocked mitochondrial electron flow, mainly at the NADH-CoQ segment, preventing ATP synthesis, which would lead to cellular death. These esters also inhibited, in the same order of potencies as respiration, the growth of 786A, TA3 and TA3-MTX-R cells in culture. In mice carrying TA3 or TA3-MTX-R tumor cells, an important decrease of the tumor growth rate and an increase of survival were observed when mice were treated with iso-butyl gallate alone or in combination with doxorubicin. These results indicate that alkyl gallates are selectively cytotoxic to tumor cells, which may be due to the mitochondrial dysfunctions of these cells.

G. Cordano

Papers

Antioxidant activity of gallates: an electrochemical study in aqueous media

Inhibition of tumoral cell respiration and growth by nordihydroguaiaretic acid.

Comparative cytotoxicity of alkyl gallates on mouse tumor cell lines and isolated rat hepatocytes.

Inhibitory effect of vanillin-like compounds on respiration and growth of adenocarcinoma TA3 and its multiresistant variant TA3-MTX-R.

Scopoletin and Hispidulin in Baccharis magellanica