Phytoestrogens and Antioxidants -- Bits of Experimental Evidence

Highlights of the Society for Integrative Oncology 1st International Conference; November 17-19, 2004; New York, NY

Sara M. Mariani, MD, PhD

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In This Article

Phytoestrogens and PC

PC is still one of the most challenging and lethal of all cancers, with a survival rate at 5 years of only 4% to 5%. The therapeutic options available are extremely limited, and these tumors usually show a poor response to chemotherapy. Hence, many are aware that new avenues for the management of patients with PC are sorely needed.

Because hopes have been raised by reports and rumors that phytoestrogen supplements might have activity against some cancers, the thought of using these compounds to treat PC has been put forward by a few researchers.[1,2,3] Preliminary experiments in mice injected subcutaneously with the PC cell line Panc-1 and treated with PC-Spes showed a slower progression of the disease vs the controls. Such improvement, however, was not associated with increased long-term survival -- the mortality rate was still 100% at days 90-100 in treated animals vs 100% at day 60 in the controls.

Is there any experimental evidence suggesting that this may be a viable therapeutic approach for PC? Do PC cells indeed express estrogen receptors (because controversial reports have been published in the past few years)? Then, what activity would phytoestrogens have on PC cells? To answer these questions, Roderich Schwarz,[4] of the Cancer Institute of New Jersey, New Brunswick, New Jersey, and colleagues undertook a detailed characterization of estrogen-receptor expression in PC cells, and an analysis of their responses to phytoestrogens in vitro and in vivo.

Estrogens may bind to 2 types of receptor in target cells: estrogen receptor-alpha (ER-alpha) and ER-beta, both of which can transactivate gene expression in target cells. As shown by Schwarz, the ratio between the mRNAs for these 2 receptors differed in different cell types. Breast cancer cells, for example, expressed very high amounts of ER-alpha and far less ER-beta, with a ratio between the 2 (ER-alpha/beta) of 204. In PC cells, such a ratio was inversed with a relatively higher expression of ER-beta vs ER-alpha (ratio, .94). The overall quantity of ER-alpha mRNA expressed by PC cells was lower than that found in ER-negative breast cancer cells ( Table 1 ).[4]

Eight PC cell lines, 7 with mutated p53 and 1 with null expression of p53, were then characterized for ER expression. Six of the 8 cell lines expressed ER-alpha protein by Western blotting, and 8 of 8 expressed ER-beta protein. All PC cell lines were treated for 48 hours with increasing concentrations of the soy isoflavone genistein or coumestrol (from 60 mcM to 10 nM), and their responses compared to that of cells treated with estradiol or tamoxifen.

Surprisingly, the PC cell lines examined showed very different responses to treatment. Genistein suppressed proliferation of Panc-1, CFPAC, and HTB cells in a dose-dependent fashion, but to everybody's surprise, it induced substantial proliferation in HTB cells at intermediate concentrations. At the "physiological" concentration of 5 mcM, genistein induced 3 different effects: suppression in Panc-1 cells, almost no effect in CFPAC cells, and extensive proliferation in HTB cells.[4]

Analysis of these data in light of ER-alpha and -beta expression revealed that there was no correlation with the absolute amounts of ER-alpha or -beta. There was, however, a direct correlation between proliferation and the ER-alpha/beta ratio: the higher the ratio, the higher the proliferation of PC cells treated with genistein or estradiol. In this spectrum, suppression of Panc-1 cell proliferation reflected its low ratio in ER-alpha/beta expression, whereas HTB-enhanced growth was associated with a high ER-alpha/beta expression ratio.[4]

In addition to the mixed suppression/proliferation data obtained with phytoestrogens, Schwarz discussed the risk of a negative interaction in PC cells between phytoestrogens and the chemotherapeutic agent gemcitabine, which at the moment is the standard agent for treatment of PC. In the presence of 10 mcM of gemcitabine, estradiol, genistein, and coumestrol, all had an inhibitory effect on the cytotoxic activity mediated by gemcitabine on PC cells, thus favoring the survival of PC cells. A higher concentration of gemcitabine (25 mcM) was not able to overcome this inhibitory effect ( Table 2 ).

Thus, Schwarz concluded: "PC cells do express ERs, but the relative ratio of ER-alpha/beta expression may significantly modify their susceptibility to treatment with phytoestrogens," leading in some PC cell lines to unexpected and unwanted proliferation at intermediate doses. The dose-dependent changes in response seen with these compounds underscore once more that dose-response studies, although time-consuming and expensive, are of critical importance in the evaluation of new anticancer agents affecting complex intracellular pathways.

No data were presented showing the effect of phytoestrogens on ex vivo PC cells, and thus it is unclear whether fresh PC tumor cells show the same heterogeneity in response to isoflavones as seen with the in vitro cell lines. In addition, other intracellular pathways, such as inactivation of the transcription factor NF-kappaB, may be involved in the activity of these compounds, and thus contribute to a complex cascade of effects.[5]

Nonetheless, although the preliminary findings in Panc-1 cells raised many hopes, the present data, although preliminary, suggest caution and indicate that further investigations should be done before in vivo treatments with phytoestrogens are undertaken in patients with PC. By the same token, awareness has to be generated on this issue among PC patients, who might choose to self-medicate.

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