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 micromol/L for primary human endothelial cells and averaged 0.3 micromol/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.
Ashimori
Naoki
N
Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, 1011 North University Room 2309, Ann Arbor, MI 48109-1078, USA.
Zeitlin
Benjamin D
BD
Zhang
Zhaocheng
Z
Warner
Kristy
K
Turkienicz
Ilan M
IM
Spalding
Aaron C
AC
Teknos
Theodoros N
TN
Wang
Shaomeng
S
Nör
Jacques E
JE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D020405:Dermis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000098:blood supply* / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016196:S Phase / Q000187:drug effects*; D013450:Sulfones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C515128:TW-37 compound; D002945:Cisplatin