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06-04-2006 | Thyroid | Article

Natural estrogen offers anaplastic thyroid cancer treatment hope


Free abstract

The naturally occurring estrogen metabolite 2-methoxyestradiol (2-ME) may offer effective therapy against anaplastic thyroid carcinoma (ATC), Swedish scientists claim.

The team makes this suggestion on finding that 2-EM treatment had strong growth inhibitory effects on human cell lines in vitro.

"ATC is one of the most malignant tumors in humans, and currently there is no effective treatment," lead author Nils-Erik Heldin, from Uppsala University, and colleagues write in the journal Thyroid.

Currently, the prognosis of ATC patients is poor, as patients will usually die from the tumor within 6-8 months. Present treatments for the condition are based on a combination of surgical resection, radiation therapy, and chemotherapy, the authors comment.

The estrogen 2-ME may be effective in the treatment of ATC, they suggest, as tumor growth inhibitory effects and antiangiogenic effects have been observed with this agent in several in vitro tumor cell systems such as in prostate cancer.

For their study, Heldin et al therefore investigated the effect of 2-ME on the growth of six human ATC cell lines (HTh7, HTh74, HTh83, C643, KAT-4, and SW1736).

Strong inhibitory effects in the presence of 2-ME were detected in all of the cell lines apart from KAT-4. Cell-cycle analyses of these lines showed that an increased fraction of these were in the G2/M phase, "indicating a G2/M-arrest in the sensitive cell lines," the researchers note.

Further analysis demonstrated that there were a high number of cells undergoing apoptosis after 2-ME treatment, with an increased activation of death receptors (DRs), caspase-3 and caspase-8. Inhibition of caspase-3 decreased the rate of apoptosis in the cells, confirming these findings.

Of note, 2-ME also increased the activity of p38 mitogen-activated protein kinase (MAPK) in the HTh7 cell line, as well as the KAT-4 cell line. Activation of stress-activated protein kinase/c-jun aminoterminal kinase was seen only in the HTh7 cells.

"The most important pathway in the 2-ME-induced ATC cell death appears to be the stress-induced mitochondrial apoptosis, but upregulation of DRs and activation of caspase-8 suggests participation of the extrinsic pathway," the investigators propose.

They conclude: "Taken together, our data demonstrate an antiproliferative and apoptotic effect of 2-ME on ATC cells involving activation of MAPKs."