Resveratrol,Thyroid Cancer,and Iodide: Drink Up?

D espite increasing controversy and concerns about its use in low risk papillary thyroid cancer, radioactive iodine (¹³¹I) remains a mainstay of therapy in high risk and advanced papillary and follicular thyroid cancers (also referred to as differentiated thyroid cancers or DTC) (1). Effective therapy of these malignancies with ¹³¹I is one of many reasons that patients with advanced, metastatic DTC enjoy prognoses that are considerably more favorable that those of other forms of cancer. However, the effectiveness of this systemic radiotherapy is limited in many patients by reduced, absent, or ineffective uptake of radioiodine. Unfortunately this is a common problem in advanced DTC both at initial diagnosis as well as at the time of recurrence or disease progression following initial therapy. Absent or ineffective uptake is also observed uniformly in anaplastic thyroid cancer (ATC).

It has been clear for several years that the impairment of iodide uptake is largely due to reduced, absent, or ineffective expression of the sodium-iodide symporter (NIS), which is responsible for iodide trapping and concentration in both benign and malignant thyroid follicular cells. Methods to enhance NIS expression and activity in DTC and ATC would offer improved therapy with ¹³¹I. Of course the most widely recognized and utilized method of enhancing NIS expression is by stimulation with either native or recombinant thyrotropin (TSH). While this practice is now widely established, it remains incompletely effective for many patients, so additional methods that can enhance or extend the TSH effect are needed. Several possible methods have been previously reported, utilizing agents that act through separate pathways or pathways that overlap the cAMP mechanism that is stimulated by TSH and the TSH receptor. One method explored extensively is “re-differentiation” therapy with retinoic acid, which has effected increased NIS expression in both thyroid follicular cells as well as breast cancer cells (2 –4), although the mechanism appears to be different between the two. This effect may be limited, however, by reduced or improper NIS trafficking to the cell membrane when examined in thyroid cancer cells (5). Despite some early enthusiasm, examination of retinoic acid in recent clinical trials in thyroid cancer has yielded only disappointing results (6 –8).

In the current issue of Thyroid, another small molecule, resveratrol, has been examined for its influence on NIS expression in thyroid cells (9). A component of red wine, resveratrol has generated considerable interest in the last several years as a potent antioxidant, antimutagenic, and antiinflammatory agent. Interest in its potential as an anticancer molecule has lead to examination of resveratrol activity in cancer clinical trials, many of which are on-going.

In the current report, the authors examined the effects of resveratrol in vitro on FRTL-5 cells, a rat thyroid cell line, with respect to iodide uptake and NIS protein expression. They observed increased levels of NIS protein, which was accompanied by enhanced uptake of radioiodine (9). This effect was additive to that of TSH and may be independent of cAMP (although this requires confirmation by use of cAMP inhibitors). Taken together, the findings suggest that resveratrol could have a role in restoring or enhancing radioiodine uptake and therapy in thyroid cancer patients who have absent or ineffective NIS expression.

Caution is warranted, however, and considerably more work is required before bringing resveratrol to the clinic for thyroid cancer. Firstly, what works in FRTL-5 cells may be ineffective in human cell lines or tumors. Examination of signaling pathways in this otherwise highly useful cell line has demonstrated that they do not behave in all respects like human thyroid cells, especially human thyroid cancer cells (10). Secondly, the magnitude of enhancement of update demonstrated by the authors was about 66%, which is not likely to result in curative radioiodine therapy for tumors that manifest very low or absent levels of NIS expression prior to resveratrol exposure. FRTL-5 cells express NIS readily, especially after TSH stimulation, and whether resveratrol can restore NIS expression in cells in which it is completely absent is unknown. Thirdly, it has not yet been demonstrated that administering resveratrol systemically (orally) in a human tumor model will have similar effects on uptake. Finally, demonstration of a beneficial effect in human clinical trials will be required to confirm these findings and to determine if increased uptake results in improved survival or clinical outcome. The disappointing findings with retinoic acid noted above should make us cautious enough to carefully evaluate each of these pieces of evidence before we ask our patients to remove the cork.

On the encouraging side is the interest in resveratrol for other tumors and diseases and the likelihood that it could be similarly tested in clinical trial for thyroid cancer in reasonably short order, assuming that additional preclinical studies are supportive. Also, the study reminds me of another recent report from the NIH-AARP Diet and Health study that reported reduced rates of thyroid cancer with increasing alcohol consumption, although not necessarily wine (11). I suspect that recruitment for clinical studies to examine these important questions will be spirited.

Cheers.