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

Abstract

Background: Heteronemin, a marine sesterterpenoid-type natural product, possesses an antiproliferative e_ect in cancer cells. In addition, heteronemin has been shown to inhibit p53 expression. Our laboratory has demonstrated that the thyroid hormone deaminated analogue, tetrac, activates p53 and induces antiproliferation in colorectal cancer. However, such drug mechanisms are still to be studied in oral cancer cells. Methods: We investigated the antiproliferative e_ects 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 and Homo Sapiens Thrombospondin 1 (THBS-1) but also cell proliferation in both OEC-M1 and SCC-25 cells. Remarkably, heteronemin increased TGF-_1 expression in SCC-25 cells. Tetrac suppressed expression of THBS-1 but not p53 expression in both cancer cell lines. Furthermore, the synergistic e_ect 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 Mar. Drugs 2020, 18, 348; doi:10.3390/md18070348 www.mdpi.com/journal/marinedrugs Mar. Drugs 2020, 18, 348 2 of 18 increased p53 phosphorylation. They also inhibited THBS-1 expression. Moreover, tetrac suppressed TGF-_expression combined with heteronemin to further enhance antiproliferation and anti-metastasis in oral cancer cells.