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Eda, Homare

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Eda, Homare

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Author's Publications: search.filters.isAuthorOfPublication.336f54af-f9a6-4337-87dd-52938ad1077d

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    Small Molecule Multi-Targeted Kinase Inhibitor RGB-286638 Triggers P53-Dependent and -Independent Anti-Multiple Myeloma Activity through Inhibition of Transcriptional CDKs
    (2014) Cirstea, Diana; Hideshima, Teru; Santo, Loredana; Eda, Homare; Mishima, Yuko; Nemani, Neeharika; Hu, Yiguo; Mimura, Naoya; Cottini, Francesca; Gorgun, Gullu; Ohguchi, Hiroto; Suzuki, Rikio; Loferer, Hannes; Munshi, Nikhil C.; Anderson, Kenneth C.; Raje, Noopur
    Small molecule multi-targeted CDK inhibitors (CDKIs) are of particular interest due to their potent antitumor activity independent of p53 gene alterations. P53 deletion is associated with a very poor prognosis in multiple myeloma (MM). In this regard, we tested the anti-MM activity of RGB-286638, an indenopyrazole-derived CDKI with Ki-nanomolar activity against transcriptional CDKs. We examined RGB-286638’s mode-of-action in MM cell lines with wild type (wt)-p53 and those expressing mutant p53. RGB-286638 treatment resulted in MM cytotoxicity in vitro associated with inhibition of MM tumor growth and prolonged survival in vivo. RGB-286638 displayed caspase-dependent apoptosis in both wt-p53 and mutant-p53 cells that was closely associated with the downregulation of RNA polymerase II phosphorylation and inhibition of transcription. RGB-286638-triggered p53 accumulation via nucleolar stress and loss of Mdm2, accompanied by induction of p53 DNA binding activity. Additionally, RGB-286638 mediated p53-independent activity, which was confirmed by cytotoxicity in p53-knockdown and p53-mutant cells. We also demonstrated downregulation of oncogenic miR-19, miR-92a-1, and miR-21. Our data provide the rationale for the development of transcriptional CDK inhibitors as therapeutic agents, which activate p53 in competent cells, while circumventing p53 deficiency through alternative p53-independent cell death mechanisms in p53-mutant/deleted cells.