Anti-tumor and anti-angiogenic effect of TW37 and Cisplatin combination therapy
Dr. Benjamin D. Zeitlin: 0000-0003-0110-0188
87th General Session & Exhibition of the IADR
International Association for Dental Research (IADR)
April 1-4, 2009
Date of Presentation
We have recently shown that Bcl-2, an anti-apoptotic and pro-angiogenic protein, is highly expressed in the blood vessels of head and neck cancer patients. Objectives: To evaluate the anti-angiogenic and anti-tumor effect of a novel small molecule inhibitor of Bcl-2 (TW37) used by itself, or in combination with Cisplatin. Methods: Sulforhodamine B (SRB) assay and propidium iodide staining followed by flow cytometry were used to characterize the cytotoxicity of TW37 and/or Cisplatin in human dermal microvascular endothelial cells (HDMEC) and in a panel of head and neck squamous cell carcinomas (HNSCC) (OSCC3, UM-SCC-11A, UM-SCC-74A). Drug effects on HDMEC and HNSCC cell cycle were evaluated by flow cytometry. Human xenografted tumors vascularized with functional human blood vessels were generated with the SCID Mouse Model of Human Tumor Angiogenesis to evaluate the effects of single drug, or TW37 and Cisplatin combination therapy, in vivo. Results: Combination therapy with TW37 and Cisplatin was more cytotoxic (P<0.05) than single drug treatment in HDMEC and the HNSCC lines evaluated here. Indeed, some of the concentrations tested showed synergistic effects of the combination of TW37 and Cisplatin. Interestingly, TW37 induced “S” phase cell cycle arrest in HDMEC and HNSCC. In vivo, combination therapy with TW37 and Cisplatin inhibited tumor progression and enhanced animal survival more effectively than single drug treatment. This was accompanied by a decrease in microvessel density and increase in tumor cell apoptosis. Conclusion: Blockade of Bcl-2 function with TW37 potentiates the effect of Cisplatin and inhibits xenografted head and neck tumor progression. These results suggest that patients with head and neck cancer might benefit from a treatment strategy that includes therapeutic inhibition of Bcl-2.
Zeitlin, B. D.,
Nör, J. E.
Anti-tumor and anti-angiogenic effect of TW37 and Cisplatin combination therapy.
Paper presented at 87th General Session & Exhibition of the IADR in Miami, FL.