The natural cytokinin 2OH3MeOBAR induces cell death by a mechanism that is different from that of the "classical" cytokinin ribosides.
Cytokinin ribosides (N6-substituted adenosines) have demonstrated anticancer activity in various cultured cell lines, several xenografts and even a small clinical trial. Effects of kinetin riboside, N6-benzyladenosine (BAR) and N6-isopentenyladenosine on various parameters related to apoptosis have also been reported, but not directly compared with those of the highly active naturally occurring aromatic cytokinins oTR (ortho-topolin riboside) and 2OH3MeOBAR (N6-(2-hydroxy-3-methoxybenzyl)adenosine). Here we show that 2OH3MeOBAR is the most active cytokinin riboside studied to date (median, 1st quartile, 3rd quartile and range of GI50 in tests with the NCI60 cell panel: 0.19, 0.10, 0.43 and 0.02 to 15.7 μM, respectively) and it differs from other cytokinins by inducing cell death without causing pronounced ATP depletion. Analysis of NCI60 test data suggests that its activity is independent of p53 status. Further we demonstrate that its 5'-monophosphate, the dominant cancer cell metabolite, inhibits the candidate oncogene DNPH1. Synthesis, purification, HPLC-MS identification and HPLC-UV quantification of 2OH3MeOBAR metabolites are also reported.
Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR & Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czechia. Electronic address: jiri.voller@upol.cz.
Jiří
J
Voller
Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czechia.
Tibor
T
Béres
Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czechia.
Marek
M
Zatloukal
The Institut Pasteur, Unité de Biologie des Bactéries Pathogènes à Gram-Positif, Centre National pour la Recherche Scientifique (CNRS) ERL 3526, 75724 Paris, France.
Pierre Alexandre
PA
Kaminski
BIOLOG Life Science Institute, Flughafendamm 9a, D-28199, Bremen, Germany.
Percy
P
Niemann
Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czechia.
Karel
K
Doležal
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77515 Olomouc, Czechia.
Petr
P
Džubák
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77515 Olomouc, Czechia.
Marián
M
Hajdúch
Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR & Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czechia.
Miroslav
M
Strnad
D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003583:Cytokinins / Q000737:chemistry / Q000494:pharmacology*; D006027:Glycosides / Q000494:pharmacology; D007541:Isopentenyladenosine / Q000494:pharmacology; D007701:Kinetin / Q000494:pharmacology; D015394:Molecular Structure
D003583:Cytokinins; D006027:Glycosides; C000614638:N6-(2-hydroxy-3-methoxybenzyl)adenosine; C527965:kinetin riboside; C575434:ortho-topolin riboside; D007541:Isopentenyladenosine; D000241:Adenosine; D007701:Kinetin
Apoptosis; Cancer; Cytokinin; Leukemia; NCI60 panel; Phytohormone