Terameprocol (Tetra-O-Methyl Nordihydroguaiaretic Acid), an Inhibitor of Sp1-Mediated Survivin Transcription, Induces Radiosensitization in Non-small Cell Lung Carcinoma

Abstract

Introduction Survivin, an inhibitor of apoptosis protein (IAP) and key regulator of mitosis, is up-regulated in a variety of cancers and is often associated with a worse prognosis. Terameprocol down-regulates the Sp1-mediated transcription of survivin and Cdk1, which is important for cell cycle progression, as well as many other proteins. Survivin inhibition has previously been shown to result in the induction of apoptosis and radiosensitization. Methods This study examined the effects of terameprocol administration on survivin transcription and expression in HCC2429 and H460 lung cancer cells. We also examined the combined effects of radiation and terameprocol on apoptosis and radiosensitivity. Results Using immunoblot analysis and luciferase assays, we confirmed that terameprocol decreases survivin transcription and protein expression. Ultimately, however, decreases in survivin expression failed to correlate with an increase in apoptosis. Nonetheless, clonogenic assay revealed that terameprocol induces increased radiosensitization in HCC2429 (DER = 1.26, p = 0.019) and H460 (DER = 1.18, p = 0.001) cells. Additionally, the data show no effect of terameprocol on cell cycle in either HCC2429 or H460 cells. Conclusions Terameprocol significantly enhances the sensitivity of non-small cell lung carcinoma cell lines to radiation therapy, although the mechanism of action remains unclear. Further study is warranted to assess the potential of terameprocol as an agent that may enhance the therapeutic ratio of radiotherapy in lung cancer.

Licochalcone A, a natural chalconoid isolated from Glycyrrhiza inflata root, induces apoptosis via Sp1 and Sp1 regulatory proteins in oral squamous cell carcinoma

“…The pro-survival protein survivin is an apoptosis inhibitor and a key regulator of mitosis, closely associated with carcinogenesis (44). Consistent with its role, it was demonstrated to be upregulated in many human cancer cells (45). Therefore, cyclin D1, survivin and Mcl-1 in cancer cells have emerged as potential therapeutic targets.…”

Discovery of Survivin Inhibitors and Beyond

“…NDGA also inhibits cyclooxygenase (COX), formyltetrahydrofolate synthetase, and carboxylesterase to a lesser extent. However, a recent study showed that although terameprocol decreases survivin transcription and protein expression, this did not correlate with an increase in apoptosis (Sun et al, 2011). 5.3).…”

MYD88-independent growth and survival effects of Sp1 transactivation in Waldenström macroglobulinemia

“…TMP is a semi-synthetic small molecule that disrupts the interaction between Sp1 and guanine-cytosinerich motifs, thereby inhibiting Sp1 transcriptional activity. 8,[18][19][20] We have observed the inhibition of Sp1 binding to known Sp1-responsive promoters by TMP using chromatin immunoprecipitation assay, and decreased expression levels of Sp1-regulated proteins, confirming that the antitumor activity of TMP in WM occurs via selective targeting of Sp1 activity.…”