title: Pharmacogenomics and analogues of the antitumour agent N6-isopentenyladenosine.
abstract: N(6)-isopentenyladenosine (i(6)A), a member of the cytokinin family of plant hormones, has potent in vitro antitumour activity in different types of human epithelial cancer cell lines. Gene expression profile analysis of i(6)A-treated cells revealed induction of genes (e.g., PPP1R15A, DNAJB9, DDIT3, and HBP1) involved in the negative regulation of cell cycle progression and reportedly up-regulated during cell cycle arrest in stress conditions. Of 6 i(6)A analogues synthesized, only the 1 with a saturated double bond of the isopentenyl side chain had in vitro antitumour activity, although weaker than that of i(6)A, suggesting that i(6)A biological activity is highly linked to its structure. In vivo analysis of i(6)A and the active analogue revealed no significant inhibition of cancer cell growth in mice by either reagent. Thus, although i(6)A may inhibit cell proliferation by regulating the cell cycle, further studies are needed to identify active analogues potentially useful in vivo.
authors.affiliation: Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Colombo
authors.forename: F Stefania
authors.initials: FS
authors.lastname: Falvella
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.forename: Graziella
authors.initials: G
authors.lastname: Pratesi
authors.forename: Pierangela
authors.initials: P
authors.lastname: Ciuffreda
authors.forename: Roberta
authors.initials: R
authors.lastname: Ottria
authors.forename: Enzo
authors.initials: E
authors.lastname: Santaniello
authors.forename: Luigi
authors.initials: L
authors.lastname: Cicatiello
authors.forename: Alessandro
authors.initials: A
authors.lastname: Weisz
authors.forename: Tommaso A
authors.initials: TA
authors.lastname: Dragani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007541:Isopentenyladenosine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D007541:Isopentenyladenosine