Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin.
Sulindac sulfone (exisulind), although a nonsteroidal anti-inflammatory drug derivative, induces apoptosis in tumor cells by a mechanism that does not involve cyclooxygenase inhibition. SW480 colon tumor cells contain guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) isoforms of the PDE5 and PDE2 gene families that are inhibited by exisulind and new synthetic analogues. The analogues maintain rank order of potency for PDE inhibition, apoptosis induction, and growth inhibition. A novel mechanism for exisulind to induce apoptosis is studied involving sustained increases in cGMP levels and cGMP-dependent protein kinase (PKG) induction not found with selective PDE5 or most other PDE inhibitors. Accumulated beta-catenin, shown to be a substrate for PKG, is decreased by exisulind, suggesting a mechanism to explain apoptosis induction in neoplastic cells harboring adenomatous polyposis coli gene mutations.
Thompson
W J
WJ
Cell Pathways, Inc., Horsham, Pennsylvania 19044, USA.
Piazza
G A
GA
Li
H
H
Liu
L
L
Fetter
J
J
Zhu
B
B
Sperl
G
G
Ahnen
D
D
Pamukcu
R
R
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015820:Cadherins / Q000378:metabolism; D003110:Colonic Neoplasms; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D007700:Kinetics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; C091517:E 4021; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D011799:Quinazolines; D015534:Trans-Activators; D051176:beta Catenin; D013467:Sulindac; D011494:Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP; C025463:sulindac sulfone