Combined Treatment of Heteronemin and Tetrac Induces Antiproliferation in Oral Cancer Cells

Background: Heteronemin, a marine sesterterpenoid-type natural product, possesses an antiproliferative effect in cancer cells. In addition, heteronemin has been shown to inhibitp53expression. Our laboratory has demonstrated that the thyroid hormone deaminated analogue, tetrac, activatesp53and induces antiproliferation in colorectal cancer. However, such drug mechanisms are still to be studied in oral cancer cells. Methods: We investigated the antiproliferative effects by Cell Counting Kit-8 and flow cytometry. The signal transduction pathway was measured by Western blotting analyses. Quantitative PCR was used to evaluate gene expression regulated by heteronemin, 3,3',5,5'-tetraiodothyroacetic acid (tetrac), or their combined treatment in oral cancer cells. Results: Heteronemin inhibited not only expression of proliferative genes andHomo Sapiens Thrombospondin 1(THBS-1) but also cell proliferation in both OEC-M1 and SCC-25 cells. Remarkably, heteronemin increasedTGF-beta 1expression in SCC-25 cells. Tetrac suppressed expression ofTHBS-1but notp53expression in both cancer cell lines. Furthermore, the synergistic effect of tetrac and heteronemin inhibited ERK1/2 activation and heteronemin also blocked STAT3 signaling. Combined treatment increased p53 protein and p53 activation accumulation although heteronemin inhibited p53 expression in both cancer cell lines. The combined treatment induced antiproliferation synergistically more than a single agent. Conclusions: Both heteronemin and tetrac inhibited ERK1/2 activation and increased p53 phosphorylation. They also inhibitedTHBS-1expression. Moreover, tetrac suppressedTGF-beta expression combined with heteronemin to further enhance antiproliferation and anti-metastasis in oral cancer cells.