The small organic compound HMN-176 delays satisfaction of the spindle assembly checkpoint by inhibiting centrosome-dependent microtubule nucleation
- Michael A. DiMaio1,
- Alexei Mikhailov2,
- Conly L. Rieder2,
- Daniel D. Von Hoff3 and
- Robert E. Palazzo12
- 1Department of Biology and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York; 2Wadsworth Center, New York State Department of Health, Albany, New York; and 3Translational Genomics Research Institute, Phoenix, Arizona
- Requests for reprints: Robert E. Palazzo, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180. Phone: 518-276-6487; Fax: 518-276-4061. E-mail: palazr{at}rpi.edu
Abstract
HMN-176 is a potential new cancer therapeutic known to retard the proliferation of tumor cell lines. Here, we show that this compound inhibits meiotic spindle assembly in surf clam oocytes and delays satisfaction of the spindle assembly checkpoint in human somatic cells by inducing the formation of short and/or multipolar spindles. HMN-176 does not affect centrosome assembly, nuclear envelope breakdown, or other aspects of meiotic or mitotic progression, nor does it affect the kinetics of Spisula or mammalian microtubule (MT) assembly in vitro. Notably, HMN-176 inhibits the formation of centrosome-nucleated MTs (i.e., asters) in Spisula oocytes and oocyte extracts, as well as from isolated Spisula or mammalian centrosomes in vitro. Together, these results reveal that HMN-176 is a first-in-class anticentrosome drug that inhibits proliferation, at least in part, by disrupting centrosome-mediated MT assembly during mitosis. [Mol Cancer Ther 2009;8(3):592–601]
Footnotes
-
↵4 Dr. Choy-Pik Chiu, Geron Corp., unpublished data.
-
↵5 Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
-
↵6 R.E. Palazzo, unpublished observations.
-
↵7 C.L. Rieder et al., unpublished observations.
-
Grant support: NIH-National Institute of General Medical Sciences grants GM43264 (R.E. Palazzo) and GM40198 (C.L. Rieder).
-
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
- Accepted December 17, 2008.
- Received September 18, 2008.
- Revision received December 5, 2008.
- American Association for Cancer Research
