Antiproliferative effect of plant cytokinin analogues with an inhibitory activity on cyclin-dependent kinases.
In this study, analogues of olomoucine, a previously described plant cytokinin analogue with cyclin-dependent kinase (CDK) inhibitory activity, were investigated for effect on CDK1 and CDK2 and for effect on cell proliferation. Eight new compounds exhibit stronger inhibitory activity on CDK1 and CDK2 and on cell proliferation than olomoucine. Some active compounds showed low inhibition of proliferation of normal myeloid growth. Improvement of inhibitory activity of known compounds with a C6-benzylamino group was brought about by substitution with one hydroxyl. Also, new C2 substituents associated with inhibitory activity on CDK and on cell proliferation are described. There was a significant correlation between effect on CDK and antiproliferative effect on the KG1 and Molt3 cell lines and on primary human lymphocytes, strongly suggesting that at least part of the antiproliferative effect of cytokinin analogues was due to inhibition of CDK activity. Cytokinin analogues induced apoptosis in a time- and concentration-dependent manner and changes in cell cycle distribution. The antiproliferative and pro-apoptotic effects of plant cytokinin analogues suggest that they are a new class of cytostatic agents and that they may find an application in the chemotherapy of cancer.
Vermeulen
K
K
Laboratory of Experimental Hematology, University of Antwerp, Antwerp University Hospital, Edegem, Belgium.
Strnad
M
M
Krystof
V
V
Havlícek
L
L
Van der Aa
A
A
Lenjou
M
M
Nijs
G
G
Rodrigus
I
I
Stockman
B
B
van Onckelen
H
H
Van Bockstaele
D R
DR
Berneman
Z N
ZN
D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003583:Cytokinins / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007701:Kinetin; D007938:Leukemia / Q000201:enzymology / Q000473:pathology*; D010944:Plants; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D003583:Cytokinins; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D011687:Purines; C090046:olomoucine; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D007701:Kinetin