The action mechanism of thalidomide on the infant cancer in a culture model

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The anti-angiogenic properties of thalidomide have led to the use of the agent as a remedy for malignant tumor, e. g., multiple myeloma, prostatic cancer, hepatoma. Nevertheless, the anti-angiogenic moiety of thalidomide remains unidentified. In 2006, I confirmed anti-angiogenic effects with treatment by thalidomide using three-dimensional collagen gel-cultures of mouse aortae. The results indicated that the anti-angiogenic effects of thalidomide stem from the anti-angiogenic action of apoptosis-inducible active caspase-3. On the basis of these data, I sought in this study to investigate the effects of thalidomide using an in vitro infant cancer model (Hepatoblastoma ; HUH-6 Clone-5) in 2007. I observed morphological and molecular biological changes of hepatoblastoma cells by thalidomide.Taken together with earlier findings, my new results indicated that the thalidomide-induced directly inhibition of proliferation of hepatoblastoma cells involved apoptosis. I demonstrated by DNA microarray that thalidomide-induced oxidative stress enhanced signaling through bone morphogenetic proteins (Bmps). This lead to up-regulation of the Bmp target gene and Wnt antagonist Dickkopf1 (DKK1) with subsequent inhibition of canonical Wnt/beta-catenin signaling and increased cell death. The apoptosis as a factor important for the mechanism of thalidomide was confirmed. From this, I conclude that perturbing of Bmp/DKK1/Wnt signaling is central to proliferation of hepatoblastoma cells of thalidomide.