Antioxidants

In the following sections, we explore the effects of an-tioxidants in general. Many issues that applied to vitamin C apply to other antioxidants as well, and our preliminary conclusions regarding their use are the same

TABLE 15.3 PROOXIDANT EFFECTS OF ANTIOXIDANTS IN VITRO

COMPOUND

COMMENT

Apigenin and luteolin

• In tests on a series of flavonoids, apigenin produced the greatest prooxidant effect independent of metal ions. Apparently, apigenin oxidized intracellular glutathione, and the oxidized glutathione then participated in the generation of additional free radicals.124, 125

• Apigenin and luteolin acted as antioxidants at low iron concentrations but as prooxidants at high iron concentrations.126

Beta-carotene

• Induced DNA damage in cancer cells via a prooxidant mechanism.127

Curcumin

• Induced DNA damage in the presence of copper.128,129

• Induced apoptosis in cancer cells through a prooxidant mechanism, and antioxidants prevented curcumin-induced apoptosis.130, 131

EGCG

• Induced apoptosis in human lung cancer cells through a prooxidant mechanism.132

Glutathione

• Glutathione (and NADH) induced DNA damage in the presence of copper through a prooxidant mechanism.69,133, 134

^/-acetylcysteine (NAC)

• Induced DNA damage in the presence of copper via a prooxidant mechanism.70

Quercetin

• Mutagenic in vitro due to its ability to induce DNA damage through a prooxidant mechanism.

• Induced DNA damage in the presence of copper via a prooxidant mechanism.135

• Produced dose-dependent cytotoxic effects due to a prooxidant mechanism.136

Vitamin A

• Retinol induced DNA damage in whole cells and in isolated DNA in the presence of copper via a prooxidant mechanism.137

Vitamin E

• Induced DNA damage in the presence of copper via a prooxidant mechanism.138

as those for vitamin C. In short, most antioxidants have the capacity to increase, decrease, or not effect cancer cell proliferation. To help assure an anticancer effect, they are best used as supportive agents within a larger combination of natural compounds and/or drugs.

In-vitro Redox Effects of Antioxidants

We begin by looking at the potential of antioxidants to act as prooxidants. Since we are not seeking a prooxidant effect, it is important to know when such an effect may be produced; it becomes more likely when single antioxidants are used and doses are large. Conversely, an antioxi-dant effect is more likely with combinations of antioxidants used at moderate oral doses.

As with vitamin C, most antioxi-dants exhibit both antioxidant and prooxidant effects in vitro, depending on conditions that include the concentration of the antioxi-dant, the presence of other anti-oxidants, and the presence of iron and copper ions. Table 15.3 summarizes some studies on the prooxidant capabilities of compounds normally considered antioxidants. Note that other compounds discussed in this book can also produce prooxidant effects. For example, omega-3 fatty acids, at high doses, can inhibit tumor growth in vivo through a prooxidant mechanism.122,123 These doses are larger than those recommended in this book, however (see Chapter 17).

In contrast to the studies listed in the table, a large number have also documented the antioxidant capabilities for each of these compounds in vitro. Thus, the data in Table 15.3 show only half the story; nonetheless, they clearly reveal that antioxidant compounds can produce prooxidant effects under the right circumstances. In light of the discussion on vitamin C, this is not surprising.

The fact that antioxidants can produce prooxidant effects in vitro complicates interpretation of some in-vitro studies on cancer cells. For example, in the studies summarized in the table, curcumin induced apoptosis in cancer cells in vitro through a prooxidant mechanism. Under normal in-vivo conditions, however, curcumin is more likely to produce an antioxidant effect. Consequently, the relevance of the curcumin studies listed, as well as those for other compounds, to in-vivo conditions is uncertain. In other words, these in-vitro studies cannot be construed as suggesting these compounds will be useful in cancer therapy. Fortunately, however, other in-vitro studies reviewed in this book do suggest their usefulness, only not as prooxidants. Indeed, their ability to act as antioxidants in most situations may support their other anticancer actions, such as inhibition of signal transduction, for example.

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