Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9. This compound also showed in vivo activity against multiple myeloma cell line KMS34 tumor xenografts in ICR/SCID mice. By means of mRNA display selection on a microfluidic chip, the target protein of TC11 was identified as nucleophosmin 1 (NPM). Binding of TC11 and NPM monomer was confirmed by surface plasmon resonance. Immunofluorescence and NPM knockdown studies in HeLa cells suggested that TC11 inhibits centrosomal clustering by inhibiting the centrosomal-regulatory function of NPM, thereby inducing multipolar mitotic cells, which undergo apoptosis. NPM may become a novel target for development of antitumor drugs active against multiple myeloma.
Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, et al. (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myeloma. Blood 109: 3489–3495.
Shaughnessy JD Jr, Zhan F, Burington BE, Huang Y, Colla S, et al. (2007) A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 109: 2276–2284.
Avet-Loiseau H, Soulier J, Fermand JP, Yakoub-Agha, Attal M, et al. (2010) Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone. Leukemia 24: 623–628.
Kurki S, Peltonen K, Latonen L, Kiviharju TM, Ojala PM, et al. (2004) Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 5: 465–475.
Amin MA, Matsunaga S, Uchiyama S, Fukui K (2008) Nucleophosmin is required for chromosome congression, proper mitotic spindle formation, and kinetochore-microtubule attachment in HeLa cells. FEBS Lett 582: 3839–3844.
Magedov IV, Manpadi M, Evdokimov NM, Elias EM, Rozhkova E, et al. (2007) Antiproliferative and apoptosis inducing properties of pyrano[3,2-c]pyridones accessible by one-step multicomponent synthesis. Bioorg Med Chem Lett 17: 3872–3876.
Otsuki T, Yamada O, Yata K, Sakaguchi H, Kurebayashi J, et al. (1999) Expression of fibroblast growth factor and FGF-receptor family genes in human myeloma cells, including lines possessing t(4;14) (q16.3;q32. 3) and FGFR3 translocation. Int J Oncol 15: 1205–1212.