The sulindac derivatives OSI-461, OSIP486823, and OSIP487703 arrest colon cancer cells in mitosis by causing microtubule depolymerization.

Abstract

Exisulind (sulindac sulfone) and three highly potent derivatives, OSI-461 (CP461), OSIP486823 (CP248), and OSIP487703, inhibit growth and induce apoptosis in SW480 human colon cancer cells, with IC(50)s of 200, 2, 0.1, and 0.003 micromol/L, respectively. The latter three compounds, but not exisulind, induce marked M-phase cell cycle arrest in these cells. This effect seems to be independent of the known ability of these compounds to cause activation of protein kinase G. When tested at twice their IC(50) concentration for growth inhibition, OSI-461, OSIP486823, and OSIP487703 cause depolymerization of microtubules in interphase cells, inhibit spindle formation in mitotic cells, and induce multinucleated cells. In vitro tubulin polymerization assays indicate that all three compounds interact with tubulin directly to cause microtubule depolymerization and/or inhibit de novo tubulin polymerization. These results suggest that the dual effects of OSI-461, OSIP486823, and OSIP487703 on impairment of microtubule functions and protein kinase G activation may explain the potent antiproliferative and apoptotic effects of these compounds in cancer cells.

• Authors: Danhua Xiao, Atsuko Deguchi, Gregg G Gundersen, Bert Oehlen, Lee Arnold, I Bernard Weinstein
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 5 Issue 1 Pg. 60-7 (Jan 2006) ISSN: 1535-7163 [Print] United States
• PMID: 16432163 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• (5-fluoro-2-methyl-1-(3,5-dimethoxy-4-hydroxybenzylidene)-3-(N-benzyl)indene)acetamide
• (5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride
• 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
• Antineoplastic Agents
• Enzyme Inhibitors
• Thionucleotides
• Tubulin
• Sulindac
• Cyclic GMP-Dependent Protein Kinases
• Cyclic GMP
• sulindac sulfone

Topics

• 3T3 Cells (drug effects)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• Cyclic GMP (analogs & derivatives, pharmacology)
• Cyclic GMP-Dependent Protein Kinases (antagonists & inhibitors, pharmacology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Mice
• Microtubules (drug effects, metabolism)
• Mitosis (drug effects)
• Spindle Apparatus (drug effects, metabolism)
• Sulindac (analogs & derivatives, pharmacology)
• Thionucleotides (pharmacology)
• Tubulin (drug effects, metabolism)
• Tumor Cells, Cultured