Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To ascertain the exact anti-myeloma mechanism of thalidomide in vivo, we performed structural development studies of thalidomide, and obtained various analogues with specific molecular properties. Among these derivatives, we found that a new thalidomide analogue, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33) had the most potent anti-myeloma effect and tubulin-polymerization-inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cell lines (RPMI8226, U266, and IM9) in a dose-dependent manner with IC50 of 1-10 microM. In contrast, thalidomide itself did not inhibit cellular growth of RPMI8226 cells. Cultivation with 10 microM 5HPP-33 induced G2/M phase cell cycle arrest, followed by apoptosis of myeloma cells. Treatment with 5HPP-33 induced caspase-3 activity and PARP cleavage. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 showed potent tubulin-polymerization-inhibiting activity with IC50 of 8.1 microM, comparable to that of the known tubulin-polymerization inhibitor, rhizoxin. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Notably, the structural requirement for its activity was critical, as other analogues and derivatives of 5HPP-33 showed only slight tubulin-polymerization-inhibiting activity. Our data suggest that 5HPP-33 is a promising candidates for a therapeutic agent of multiple myeloma. In addition, these results suggest that the tubulin-polymerization inhibiting activity of thalidomide might be a possible mechanism for inducing the apoptosis of myeloma cells by thalidomide.
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PMID:Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: possible anti-myeloma mechanism of thalidomide. 1820 82

Despite the conventional and high-dose chemotherapy with hematopoietic stem cell transplantation, multiple myeloma eventually relapses, resulting in an incurable hematological malignancy. Therefore, novel therapeutic approaches in clinical settings are desired. Recently, thalidomide was introduced for the treatment of myeloma, and many clinical trials have since confirmed its efficacy in patients with relapsed/refractory or newly diagnosed multiple myeloma. Multiple mechanisms have been proposed to explain thalidomide's anti-myeloma activity. However, the precise mechanism underlying this activity remains unclear, because thalidomide rapidly undergoes spontaneous, nonenzymatic, hydrolytic cleavage to numerous metabolites in vivo. To elucidate the exact anti-myeloma mechanism of thalidomide in vivo, we have performed structural development studies of thalidomide, and obtained various analogs with specific molecular properties. Among these derivatives, we found that a new thalidomide analog, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33), has the most potent anti-myeloma effect with tubulin polymerization inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cells in a dose-dependent manner with IC(50) of 1-10 microM. In contrast, thalidomide itself did not inhibit RPMI8226 cell growth. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 had potent tubulin polymerization inhibiting activity with IC(50) of 8.1 microM, comparable to that of rhizoxin, a known tubulin polymerization inhibitor. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Our data suggest that 5HPP-33 is a promising candidate as a therapeutic agent for multiple myeloma. In addition, the results suggest that thalidomide's tubulin polymerization inhibiting activity might be the mechanism underlying the induction of apoptosis in myeloma cells.
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PMID:New tubulin polymerization inhibitor derived from thalidomide: implications for anti-myeloma therapy. 1839 44

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.
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PMID:A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. 2276 10