title: Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity.
abstract: Knockout and transgenic studies in mice demonstrate that normal somatic tissues redundantly express 3 cyclin D proteins, whereas tumor cells seem dependent on a single overexpressed cyclin D. Thus, selective suppression of the individual cyclin D deregulated in a tumor represents a biologically valid approach to targeted cancer therapy. In multiple myeloma, overexpression of 1 of the cyclin D proteins is a ubiquitous feature, unifying at least 7 different initiating genetic events. We demonstrate here that RNAi of genes encoding cyclin D1 and cyclin D2 (CCND1 and CCND2, respectively) inhibits proliferation and is progressively cytotoxic in human myeloma cells. By screening a chemical library using a cell-based assay for inhibition of CCND2 trans-activation, we identified the plant cytokinin kinetin riboside as an inhibitor of CCND2 trans-activation. Kinetin riboside induced marked suppression of CCND2 transcription and rapidly suppressed cyclin D1 and D2 protein expression in primary myeloma cells and tumor lines, causing cell-cycle arrest, tumor cell-selective apoptosis, and inhibition of myeloma growth in xenografted mice. Mechanistically, kinetin riboside upregulated expression of transcription repressor isoforms of cAMP-response element modulator (CREM) and blocked both trans-activation of CCND2 by various myeloma oncogenes and cis-activation of translocated CCND1, suggesting induction of an overriding repressor activity that blocks multiple oncogenic pathways targeting cyclin D genes. These data support targeted repression of cyclin D genes as a therapeutic strategy for human malignancies.
authors.affiliation: Mayo Clinic, Comprehensive Cancer Center, Division of Hematology and Oncology, Scottsdale, Arizona, USA.
authors.forename: Rodger E
authors.initials: RE
authors.lastname: Tiedemann
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
authors.forename: Chang-Xin
authors.initials: CX
authors.lastname: Shi
authors.forename: Yuan Xiao
authors.initials: YX
authors.lastname: Zhu
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Palmer
authors.forename: Michael
authors.initials: M
authors.lastname: Sebag
authors.forename: Ron
authors.initials: R
authors.lastname: Marler
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects; D056741:Cyclin D; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007701:Kinetin / Q000235:genetics* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D009705:Nucleosides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; C080336:CCND2 protein, human; D056741:Cyclin D; D056742:Cyclin D2; D016213:Cyclins; D009705:Nucleosides; D007701:Kinetin