Prevention and treatment of cancer with indole-3-carbinol

Alternative Medicine Review, Dec, 2001 by Matthew S. Brignall

Abstract

Indole-3- (I-3-C) is a naturally occurring constituent of many plant foods. Oral administration of I-3-C has been shown to manipulate estrogen metabolism in humans in a possibly beneficial manner. I-3-C increases the 2/16-hydroxyestrone ratio, a ratio found to be predictive of breast cancer risk in some prospective studies. Animal and in vitro studies have identified a number of other possibly beneficial effects of I-3-C and its metabolites, including inhibition of estrogen binding and modulation of oncogene expression. A chemopreventive effect of I-3-C has been demonstrated in a number of animal models. Some chemical carcinogenesis models have found a tumor promoting effect of I-3-C, however. Epidemiological studies support the hypothesis that high intakes of I-3-C may have broad chemopreventive effect. Preliminary human trials have demonstrated that I-3-C is well tolerated and has a sustained estrogen modifying effect. I-3-C is a good candidate for clinical trial in women at increased risk of developing breast cancer.

(Altern Med Rev 2001:6(6):580-589)

Introduction

Indole-3-carbinol (I-3-C) is a compound found in high concentrations in Brassica vegetables, including broccoli, cauliflower, Brussels sprouts, and cabbage. It has received attention in recent years as a promising preventive and treatment agent for breast and other types of cancers.

I-3-C (Figure 1) has recently become available as a nutritional supplement. Preliminary studies have examined its safety and attempted to elucidate an optimal dose. Early studies have been promising, and will likely be followed up with larger clinical trials. This paper will examine the evidence supporting the use of I-3-C for prevention and treatment of cancer from human, animal, and in vitro studies. It will also review the metabolism and safety of oral I-3-C.

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Absorption/Metabolism

Animal studies have shown that intravenous or intraperitoneal administration of I-3-C does not have the effect that is seen with oral dosing. (1) This suggests that other metabolic products are largely responsible for the action of I-3-C. Two metabolic products of I-3-C, diindolylmethane (DIM) and indolylcarbazole (ICZ) have received the most attention as active constituents, although there are a number of other metabolites of I-3-C that have yet to be fully investigated. (2) Another major metabolic product, 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr-1, also referred to as BII), has recently become of interest.

Following oral administration of 400 mg I-3-C to humans, serum levels of DIM reached between 0.1 and 0.4 mcg/mL. (3) Serum I-3-C was not measurable at this dosage. Presence or absence of other products, such as LTr-1 or ICZ was not reported.

Animal studies have shown DIM and LTr-1 to be the major serum metabolites following oral administration of I-3-C, (4) although other metabolites are measurable in smaller amounts on high performance liquid chromatography (HPLC). DIM and LTr-1 levels were roughly equivalent, with different metabolites being more prevalent in different organs. Another study quantified hepatic concentrations of I-3-C metabolites, finding 24-perent DIM, 20-percent LTr-1, 24-percent of another metabolite called 1-(3-hydroxymethyl)-indolyl-3-indolylmethane, and a number of minor metabolites. (5) In this latter study, the potent metabolite ICZ was found in very small concentrations, at an order of magnitude smaller than the major metabolites.

Different conditions in the gastrointestinal tract may favor production of different metabolites. Formation of LTr-1 is pH dependent, with declining production at pH above 4.5. (4) DIM production increases at pH levels above 3. (4)

Initially, the major route of elimination of I-3-C metabolites is urinary. After 40 hours of continuous dietary administration, however, the fecal route becomes prevalent. (5) I-3-C metabolites have a serum half-life greater than 48 hours after a week of continuous administration in animal studies. (5)

In vitro/In vivo Mechanisms of Action

Indole-3-carbinol has a number of potential mechanisms of action for chemoprevention of cancer. It was one of only eight compounds (including ascorbic acid, vitamin E succinate, and folic acid) found to have benefit in six different in vitro chemoprevention models in a National Cancer Institute screening study. (6) While many mechanisms have been described, it is possible others exist, particularly among the minor I-3-C metabolites that have not been well studied.

Several studies have examined the effects of I-3-C and its metabolites on breast cancer cell lines. I-3-C and tamoxifen have been shown to act separately and/or cooperatively to inhibit the growth of estrogen receptor-positive (ER ) breast cancer cells. (7) Tamoxifen and I-3-C appeared to function by different mechanisms. I-3-C can stimulate apoptosis in estrogen receptor-negative human breast cancer cell lines as well. (8)

DIM (Figure 2) has been shown to inhibit proliferation of human breast cancer cells at concentrations achievable through oral supplementation with I-3-C (10-50 microM). (9) Incubation of human breast cancer cells with DIM has been found to stimulate apoptosis. (10) In this study, the apoptosis-promoting activity of DIM was found to be p53 independent.