Predicting the physiological relevance of in vitro cancer preventive activities of phytochemicals

Abstract

There is growing interest in the ability of phytochemicals to prevent chronic diseases, such as cancer and heart disease. However, some of these agents have poor bioavailability and many of the in‐depth studies into their mechanisms of action have been carried out in vitro using doses which are unachievable in humans. In order to optimize the design of chemopreventive treatment, it is important to determine which of the many reported mechanisms of action are clinically relevant. In this review we consider the physiologically achievable doses for a few of the best studied agents (indole‐3‐carbinol, diindolylmethane, curcumin, epigallocatechin‐3‐gallate and resveratrol) and summarize the data derived from studies using these low concentrations in cell culture. We then cite examples of in vitro effects which have been observed in vivo. Finally, the ability of agent combinations to act synergistically or antagonistically is considered. We conclude that each of the compounds shows an encouraging range of activities in vitro at concentrations which are likely to be physiologically relevant. There are also many examples of in vivo studies which validate in vitro observations. An important consideration is that combinations of agents can result in significant activity at concentrations where any single agent is inactive. Thus, for each of the compounds reviewed here, in vitro studies have provided useful insights into their mechanisms of action in humans. However, data are lacking on the full range of activities at low doses in vitro and the benefits or otherwise of combinations in vivo.

Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells

“…Concentrations of phytochemicals were 3 Amol/L curcumin, 10 Amol/L 3,3 ¶-diindolylmethane (DIM), 8 Amol/L epigallocatechin gallate (EGCG), 2.5 Amol/L genistein, and 30 Amol/L indole-3-carbinol (I3C). Comparable serum concentrations for curcumin (1.77 F 1.87 Amol/L), DIM (20 Amol/L), EGCG (0.29 -7.7 Amol/L), genistein (2.5 F 1.6 Amol/L), and I3C (28 Amol/L) were detected in humans and/or animal models (4,5).…”

The role of herbs and spices in cancer prevention

“…Cyclin D1 over-expression has been linked with breast, esophageal, head, neck, and prostate cancers (77). There are always concerns about how to interpret in vitro studies because of issues related to physiologically relevant concentrations and bioavailability (94,95).…”

Indole-3-carbinol enhances anti-proliferative, but not anti-invasive effects of oxaliplatin in colorectal cancer cell lines

“…However, the marked decrease in proliferative capacity combined with a decreased nuclear signalling pool of β-catenin and increases in the tumour suppressor E-cadherin warrants further investigation regarding the potential of this combination. A number of studies have clearly demonstrated that I3C is biologically active in animals and humans [10] so it will be crucial to determine whether the effects reported here can also be replicated in vivo and most importantly, within a clinical context. …”

“…I3C is currently in clinical trial for treatment of recurrent respiratory papillomatosis [5,6] and cervical intraepithelial neoplasia [7,8] and has been shown to be well tolerated at doses up to 400mg/day [9]. Pharmacokinetic studies of I3C disposition have revealed systemic doses of up to 170μmol/L in tissue [10], which equates with in vitro efficacy particularly in the liver [11,12] which along with lymph nodes [13,14], is the major site for colorectal metastasis. I3C has been shown to exhibit both anti-proliferative and anti-invasive potential [15] via a variety of mechanisms, including up-regulation of E-cadherin and β-catenin at the cytoplasmic membrane [16,17], concurrent with down-regulation of nuclear β-catenin levels.…”