Abstract
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.
Highlights
Multiple myeloma is one of the hematopoietic organ tumors which is characterized by the monoclonal proliferation of malignant plasma cells, resulting in appearance of serum or urinary monoclonal protein [1,2,3]
To identify the most potent compound, we investigated the ability of the hit compounds from the first screening to inhibit proliferation or to induce apoptosis of several multiple myeloma cell lines
The results indicated that TC11 required a lower concentration or a shorter treatment time to induce apoptosis of several multiple myeloma cell lines (Figure S2B)
Summary
Multiple myeloma is one of the hematopoietic organ tumors which is characterized by the monoclonal proliferation of malignant plasma cells, resulting in appearance of serum or urinary monoclonal protein [1,2,3]. Tumor cells derived from high-risk patients have deletion of chromosome 17 (del 17), on which the p53 tumor suppressor gene is located, deletion of chromosome 13 or chromosomal translocation t(4;14) accompanied with constitutive activation of FGFR-3 on chromosome 4 [9,10,11]. Development of novel drugs which are active against multiple myeloma cells with these high-risk chromosomal or genetic alterations is necessary to improve the prognosis. Elucidation of the mechanisms of growth suppression of multiple myeloma cells is expected to improve our understanding of the molecular pathogenesis of multiple myeloma. Our aim in this study was to find a novel anti-tumor drug for multiple myeloma and to elucidate its molecular mechanism of action
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