Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity.
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.
Tiedemann
Rodger E
RE
Mayo Clinic, Comprehensive Cancer Center, Division of Hematology and Oncology, Scottsdale, Arizona, USA.
Mao
Xinliang
X
Shi
Chang-Xin
CX
Zhu
Yuan Xiao
YX
Palmer
Stephen E
SE
Sebag
Michael
M
Marler
Ron
R
Chesi
Marta
M
Fonseca
Rafael
R
Bergsagel
P Leif
PL
Schimmer
Aaron D
AD
Stewart
A Keith
AK
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
D000970:Antineoplastic Agents; C080336:CCND2 protein, human; D056741:Cyclin D; D056742:Cyclin D2; D016213:Cyclins; D009705:Nucleosides; D007701:Kinetin