Cancer Therapy

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TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and invasion in pancreatic cancer†

  1. Zhiwei Wang1,
  2. Wen Song2,
  3. Amro Aboukameel2,
  4. Mussop Mohammad2,
  5. Guoping Wang3,
  6. Sanjeev Banerjee1,
  7. Dejuan Kong1,
  8. Shaomeng Wang3,
  9. Fazlul H. Sarkar1,
  10. Ramzi M. Mohammad2,‡,*

Article first published online: 4 JUN 2008

DOI: 10.1002/ijc.23610

Issue

International Journal of Cancer

International Journal of Cancer

Volume 123, Issue 4, pages 958–966, 15 August 2008

Additional Information

How to Cite

Wang, Z., Song, W., Aboukameel, A., Mohammad, M., Wang, G., Banerjee, S., Kong, D., Wang, S., Sarkar, F. H. and Mohammad, R. M. (2008), TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and invasion in pancreatic cancer. Int. J. Cancer, 123: 958–966. doi: 10.1002/ijc.23610

Author Information

  1. 1

    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI

  2. 2

    Department of Internal Medicine, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI

  3. 3

    Department of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI

  1. ‡

    Fax: +313-576-8389.

*Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, 732 HWCRC, 4100 John R. Street, Detroit, MI 48201

  1. †

    Conflict of Interest: University of Michigan has filed a patent on TW-37, which has been licensed by Ascenta Therapeutics Inc. University of Michigan and Dr. Shaomeng Wang own equity in Ascenta. Dr. Shaomeng Wang also serves as a consultant for Ascenta and is the principal investigator on research contract from Ascenta to University of Michigan.

Publication History

  1. Issue published online: 12 JUN 2008
  2. Article first published online: 4 JUN 2008
  3. Manuscript Accepted: 11 MAR 2008
  4. Manuscript Received: 7 JUL 2007

Funded by

  • National Cancer Institute, NIH. Grant Number: R01CA109389
  • NIH. Grant Number: 5R01CA101870
  • NIH. Grant Number: P30CA22453
  • NIH. Grant Number: U19CA11317
  • Department of Defense Breast Cancer Program. Grant Number: BC0009140

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Keywords:

  • Bcl-2;
  • NF-κB;
  • pancreatic cancer;
  • invasion;
  • angiogenesis

Abstract

Bcl-2 family of proteins plays critical roles in human cancers, including pancreatic cancer, suggesting that the discovery of specific agents targeting Bcl-2 family proteins would be extremely valuable for pancreatic cancer therapy. We have previously reported the synthesis and characterization of TW-37, which seems to be a negative regulator of Bcl-2. In this investigation, we tested our hypothesis whether TW-37 could be an effective inhibitor of cell growth, invasion and angiogenesis in pancreatic cancer cells. Using multiple cellular and molecular approaches such as MTT assay, apoptosis enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blotting, electrophoretic mobility shift assay for measuring DNA binding activity of NF-κB, migration, invasion and angiogenesis assays, we found that TW-37, in nanomolar concentrations, inhibited cell growth in a dose- and time-dependent manner. This was accompanied by increased apoptosis and concomitant attenuation of NF-κB, and downregulation of NF-κB downstream genes such as MMP-9 and VEGF, resulting in the inhibition of pancreatic cancer cell migration, invasion and angiogenesis in vitro and caused antitumor activity in vivo. From these results, we conclude that TW-37 is a potent inhibitor of progression of pancreatic cancer cells, which could be due to attenuation of Bcl-2 cellular signaling processes. Our findings provide evidence showing that TW-37 could act as a small-molecule Bcl-2 inhibitor on well-characterized pancreatic cancer cells in culture as well as when grown as tumor in a xenograft model. We also suggest that TW-37 could be further developed as a potential therapeutic agent for the treatment of pancreatic cancer. © 2008 Wiley-Liss, Inc.

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