Search

Supplementary Data from TW-37, a small-molecule inhibitor of Bcl-2, mediates S-phase cell cycle arrest and suppresses head and neck tumor angiogenesis

Members of the Bcl-2 family play a major role in the pathobiology of head and neck cancer. We have shown that Bcl-2 orchestrates a cross talk between tumor cells and endothelial cells that have a direct effect on the progression of head and neck squamous cell carcinoma (HNSCC). Notably, Bcl-2 is significantly up-regulated in the tumor-associated endothelial cells compared with the endothelial cells of normal oral mucosa in patients with HNSCC. Here, we evaluated the effect of TW-37, a small-molecule inhibitor of Bcl-2, on the cell cycle and survival of endothelial cells and HNSCC and on the progression of xenografted tumors. TW-37 has an IC50 of 1.1 μmol/L for primary human endothelial cells and averaged 0.3 μmol/L for head and neck cancer cells (OSCC3, UM-SCC-1, and UM-SCC-74A). The combination of TW-37 and cisplatin showed enhanced cytotoxic effects for endothelial cells and HNSCC in vitro, compared with single drug treatment. Notably, whereas cisplatin led to an expected G2-M cell cycle arrest, TW-37 mediated an S-phase cell cycle arrest in endothelial cells and in HNSCC. In vivo, TW-37 inhibited tumor angiogenesis and induced tumor apoptosis without significant systemic toxicities. Combination of TW-37 and cisplatin enhanced the time to tumor failure (i.e., 4-fold increase in tumor volume), compared with either drug given separately. Collectively, these data reveal that therapeutic inhibition of Bcl-2 function with TW-37 is sufficient to arrest endothelial cells and HNSCC in the S phase of the cell cycle and to inhibit head and neck tumor angiogenesis.[Mol Cancer Ther 2009;8(4):893–903]

Supplementary Figures from TW-37, a small-molecule inhibitor of Bcl-2, mediates S-phase cell cycle arrest and suppresses head and neck tumor angiogenesis

PDF fiel - 765K

PDF file - 6.7MB

Bcl-2 is an antiapoptotic protein that has also been found to function as a proangiogenic signaling molecule. Improvements in antiangiogenic therapy can be engendered by metronomic dosing. Thus, we hypothesized that BH3-mimetic drugs that antagonize Bcl-2 family proteins may exert a greater efficacy when dosed metronomically. To examine this hypothesis, we employed AT101, an orally available and well-tolerated BH3-mimetic drug that has been established as effective. In a mouse xenograft model of human squamous cell carcinomas (SCC) that includes a humanized vasculature, we explored the effects of docetaxel in combination with either daily (metronomic) or weekly (bolus) doses of AT101. In addition, we explored the effect of single or combination therapy on angiogenesis and survival of endothelial or SCC cells in vitro. Metronomic AT101 therapy increased mouse survival, decreased tumor mitotic index, and decreased tumor microvessel density, compared with bolus therapy. Therapeutic potentiation was achieved by similar overall drug exposure and without altering systemic toxicities. Combinations of AT101 and docetaxel produced additive toxicity in both endothelial and SCC tumor cells. Notably, subapoptotic concentrations of AT101 potently inhibited the angiogenic potential of endothelial cells. Taken together, our findings unveil the efficacious benefits that can be achieved by metronomic delivery of BH3-mimetic drugs, in particular suggesting that SCC patients with might benefit from low-dose continuous administration of these drugs. Cancer Res; 72(3); 716–25. ©2011 AACR.

PDF file - 9.2K

PDF file - 59K

PDF file - 9.8K

Computer-based learning applications and mobile technology have transformed many aspects of the educational experience over the last decade, producing software aimed at improving learning efficiency and streamlining the presentation of course materials. One such class of software, purpose-created to take advantage of spaced learning and spaced testing principles, are electronic flashcard applications. We provide a perspective on the novel use of the Quizlet flashcard application in a tertiary educational setting. To reduce cognitive load for international graduate dental students taking a pharmacology review course, we implemented Quizlet, which integrates both spaced learning and self-testing, to improve the student learning experience. This study assessed students' perceptions of the Quizlet flashcard system in a student cohort comprised of two consecutive years' classes (n = 51 students in total). Results indicated broad acceptance of Quizlet based on ease of use of the software and ease of study of the material. Our data provide insight into the use of this common software in a professional healthcare tertiary education setting and further demonstrate the successful application of electronic flashcards for a mixed international student cohort. Further research should include an assessment of the impact of flashcard on long-term knowledge retention in this setting.The online version contains supplementary material available at 10.1007/s10639-022-11371-3.