Terameprocol (tetra-O-methyl nordihydroguaiaretic acid), an inhibitor of Sp1-mediated survivin transcription, induces radiosensitization in non-small cell lung carcinoma.
BACKGROUND
Survivin, an inhibitor of apoptosis protein 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 and 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 (dose enhancement ratio = 1.26, p = 0.019) and H460 (dose enhancement ratio = 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.
Department of Radiation Oncology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-5671, USA.
Yunguang
Y
Sun
Nicholas J
NJ
Giacalone
Bo
B
Lu
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D000077022:Survivin; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D011838:Radiation-Sensitizing Agents; D016329:Sp1 Transcription Factor; D000077022:Survivin; C076852:terameprocol; D009637:Masoprocol