Antioxidants Accelerate Lung Cancer Progression in Mice

Trizah K. Milugo and Joel W. Ochieng, Center for Biotechnology and Bioinformatics, College of Agriculture and Veterinary Sciences, University of Nairobi P. O. Box 30197 Nairobi, 00100.

Correspondence to: jochieng@uonbi.ac.ke Tel: +254 711 121359

Antioxidants are chemical compounds that can prevent oxidation of other molecules by donating electrons, thereby neutralizing free radicals that may otherwise damage DNA and promote tumorigenesis. The effect of antioxidants on cancer is inconsistent in the literature (1, 2). Now, a landmark study published in this Journal by (3) suggests that antioxidants accelerate progression in lung cancer by reducing ROS, DNA damage and expression of p53 gene. They hypothesized that a feedback mechanism in lung cells down-regulates the endogenous ROS defense system when the amounts of ROS are suppressed. That antioxidants may harm persons already exhibiting cancer may be plausible; however, we offer an alternative explanation to the mechanism of action:

Reversed pH gradient more parsimonious than feedback mechanism: Empirical studies have shown tumor extracellular environment to be more acidic than the intracellular, creating a reversed pH gradient across the cell membrane (4). This gradient is maintained by secretion of protons (H+) to the extracellular environment by tumor cells (4), and increases with tumor aggressiveness (5). The Vitamin E used in the experiment (DL- alpha-Tocopheryl Acetate) is a synthetic acid with a hydroxyl group that donates hydrogen atom to the extracellular environment, lowering the PH, further increasing the intracellular-extracellular pH gradient which then lowers ROS and accelerates proliferation of the cells as observed by (3). Sustained changes in pH gradient may be the mechanism responsible for natural reduction of ROS, required for proliferation to progress in victims without antioxidant supplementation. Apart from human systems, cell growth associated with changes in extracellular pH and ROS has been demonstrated in Arabidopsis (6), where increasing extracellular pH arrested root hair elongation; decreasing pH elicited bursting at the tip. Similarly, application of exogenous ROS arrested elongation.

Increased pH inhibited expression of p53 gene: The authors (3) hypothesized that antioxidants reduced expression of p53 by suppressing the amounts of ROS, thereby causing down-regulation of the endogenous ROS defense system. We propose that the increase of pH by antioxidants lowered the expression of the endogenous p53 gene. Numerous reports have shown p53 expression to be enhanced at lower pH and vice versa (7).

Unpurified antioxidants may not speed cancer progression: Looked at casually, this publication may discourage efforts targeting antioxidant rich plants to isolate a possible cancer cure. In most parts of the developing world, antioxidants are often taken as herbal medicine and infusion in hot drinks. In such unpurified state, interaction among phytochemicals in plant extracts does affect their activity and cytotoxicity as shown in a recent analysis of quinine tree, where co- occurrence of alkaloids and saponins significantly reduced activity (8). Hence the outcome of (3) experiments may apply to pure compounds such as Vitamin E, but not to crude extracts. Despite this latest experiment showing that these products may not be suited for pre-existing cases of cancer, further bioactivity and toxicity evaluations should be encouraged, as the published data may only apply to two commercially prepared and purified food supplements.

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