Anticancer activity of natural cytokinins: a structure-activity relationship study.
Cytokinin ribosides (N(6)-substituted adenosine derivatives) have been shown to have anticancer activity both in vitro and in vivo. This study presents the first systematic analysis of the relationship between the chemical structure of cytokinins and their cytotoxic effects against a panel of human cancer cell lines with diverse histopathological origins. The results confirm the cytotoxic activity of N(6)-isopentenyladenosine, kinetin riboside, and N(6)-benzyladenosine and show that the spectrum of cell lines that are sensitive to these compounds and their tissues of origin are wider than previously reported. The first evidence that the hydroxylated aromatic cytokinins (ortho-, meta-, para-topolin riboside) and the isoprenoid cytokinin cis-zeatin riboside have cytotoxic activities is presented. Most cell lines in the panel showed greatest sensitivity to ortho-topolin riboside (IC(50)=0.5-11.6 microM). Cytokinin nucleotides, some synthesized for the first time in this study, were usually active in a similar concentration range to the corresponding ribosides. However, cytokinin free bases, 2-methylthio derivatives and both O- and N-glucosides showed little or no toxicity. Overall the study shows that structural requirements for cytotoxic activity of cytokinins against human cancer cell lines differ from the requirements for their activity in plant bioassays. The potent anticancer activity of ortho-topolin riboside (GI(50)=0.07-84.60 microM, 1st quartile=0.33 microM, median=0.65 microM, 3rd quartile=1.94 microM) was confirmed using NCI(60), a standard panel of 59 cell lines, originating from nine different tissues. Further, the activity pattern of oTR was distinctly different from those of standard anticancer drugs, suggesting that it has a unique mechanism of activity. In comparison with standard drugs, oTR showed exceptional cytotoxic activity against NCI(60) cell lines with a mutated p53 tumour suppressor gene. oTR also exhibited significant anticancer activity against several tumour models in in vivo hollow fibre assays.
Voller
Jirí
J
Laboratory of Growth Regulators, Palacký University and Institute of Experimental Botany ASCR, Slechtitelů 11, 783 71 Olomouc, Czech Republic.
Zatloukal
Marek
M
Lenobel
René
R
Dolezal
Karel
K
Béres
Tibor
T
Krystof
Vladimír
V
Spíchal
Lukás
L
Niemann
Percy
P
Dzubák
Petr
P
Hajdúch
Marián
M
Strnad
Miroslav
M
D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003583:Cytokinins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D007541:Isopentenyladenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D007701:Kinetin / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D054547:National Cancer Institute (U.S.); D010937:Plant Growth Regulators / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014481:United States
D000970:Antineoplastic Agents; D003583:Cytokinins; D010937:Plant Growth Regulators; C527965:kinetin riboside; C017061:N(6)-benzyladenosine; D007541:Isopentenyladenosine; C009699:zeatin riboside; D000241:Adenosine; D007701:Kinetin