The sulindac derivatives OSI-461, OSIP486823, and OSIP487703 arrest colon cancer cells in mitosis by causing microtubule depolymerization.
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.
Xiao
Danhua
D
Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, 701 West 168th Street, Room 1509, New York, NY 10032, USA.
Deguchi
Atsuko
A
Gundersen
Gregg G
GG
Oehlen
Bert
B
Arnold
Lee
L
Weinstein
I Bernard
IB
D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
C508487:(5-fluoro-2-methyl-1-(3,5-dimethoxy-4-hydroxybenzylidene)-3-(N-benzyl)indene)acetamide; C439285:(5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride; C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013873:Thionucleotides; D014404:Tubulin; D013467:Sulindac; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; C025463:sulindac sulfone