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)

The initial treatment of multiple myeloma (MM) experienced a paradigm shift, in the past decade, with the introduction of novel agents such as thalidomide, lenalidomide and bortezomib, leading to improved outcomes. High dose therapy and autologous stem cell transplantation remain an important therapeutic option for patients with MM eligible for the procedure. However, most of these treatment regimens are too expensive for Chinese patients. Therefore, we investigated the effects of artesunate, which is commonly used in the treatment of severe malaria, on inhibition of proliferation and induction of apoptosis of a mouse myeloma cell line SP2/0. The growth inhibition of SP2/0 cell proliferation induced by artesunate (ART) treatment was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and the rate of apoptosis and cell cycle changes induced by ART were analyzed by flow cytometry. ART-induced morphology changes of apoptosis in SP2/0 cells, as observed by light and transmission electron microscopy. Additionally, DNA laddering, which is a hallmark of apoptosis, was observed by agarose gel electrophoresis of DNA harvested from SP2/0 cells treated with ART. The levels of nuclear factor kappa B p65 (NFkappaB p65) protein in nucleus and the inhibitor of NFkappaB (IkappaBalpha) in the cytoplasm were measured by western blot analysis and ELISA to evaluate NFkappaB p65 transcription activity indirectly. The results show that artesunate inhibited the proliferation and induced apoptosis of SP2/0 cells in a dose- and time-dependent manner. Artesunate also increased the proportion of SP2/0 cells in G0/G1 phase, while decreased the proportion of cells in G2/M or S phase. Additionally, artesunate treatment decreased the level of NFkappaB p65 protein in the nucleus, while increased the level of IkappaBalpha protein in the cytoplasm. The present result is the first report to show that artesunate may be useful in the treatment of MM.
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PMID:Effect of artesunate on inhibiting proliferation and inducing apoptosis of SP2/0 myeloma cells through affecting NFkappaB p65. 1972 25

The green tea constituent, (-)-epigallocatechin-3-gallate (EGCG), has chemopreventive and anticancer effects. This is partially because of the selective ability of EGCG to induce apoptosis and death in cancer cells without affecting normal cells. In the present study, the activity of EGCG against the myeloma cell line, KM3, was examined. Our results demonstrated, for the first time, that the treatment of the KM3 cell line with EGCG inhibits cell proliferation and induces apoptosis, and there is a synergistic effect when EGCG and bortezomib are combined. Further experiments showed that this effect involves the NF-kappaB pathway. EGCG inhibits the expression of the P65 mRNA and P65/pP65 protein, meanwhile it downregulates pIkappaBalpha expression and upregulates IkappaBalpha expression. EGCG also activates caspase-3, -8, cleaved caspase-9, and poly-ADP-ribose polymerase (PARP) and subsequent apoptosis. These findings provided experimental evidence for efficacy of EGCG alone or in combination with bortezomib in multiple myeloma therapy.
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PMID:Potentiation of (-)-epigallocatechin-3-gallate-induced apoptosis by bortezomib in multiple myeloma cells. 2001 76

Agents that can enhance tumor cell apoptosis and inhibit invasion have potential for the treatment of cancer. Here, we report the identification of escin, a pentacyclic triterpenoid from horse chestnut that exhibits antitumor potential against leukemia and multiple myeloma. Whether examined by esterase staining, phosphatidyl-serine staining, DNA breakage, or caspase-mediated poly(ADP-ribose) polymerase cleavage, escin potentiated tumor necrosis factor (TNF)-induced apoptosis but inhibited tumor cell invasion. This correlated with the down-regulation of bcl-2, cellular inhibitor of apoptosis protein-2, cyclin D1, cyclooxygenase-2, intercellular adhesion molecule-1, matrix metalloproteinase-9, and vascular endothelial growth factor, which are all regulated by the activation of the transcription factor NF-kappaB. When examined by electrophoretic mobility shift assay, the triterpenoid suppressed nuclear factor-kappaB (NF-kappaB) activation induced by TNF and other inflammatory agents, and this correlated with the inhibition of IkappaBalpha phosphorylation and degradation, inhibition of IkappaB kinase complex (IKK) activation, suppression of p65 phosphorylation and nuclear translocation, and abrogation of NF-kappaB-dependent reporter activity. Overall, our results demonstrate that escin inhibits activation of NF-kappaB through inhibition of IKK, leading to down-regulation of NF-kappaB-regulated cell survival and metastatic gene products and thus resulting in sensitization of cells to cytokines and chemotherapeutic agents.
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PMID:Escin, a pentacyclic triterpene, chemosensitizes human tumor cells through inhibition of nuclear factor-kappaB signaling pathway. 2010 8

GCS-100 is a galectin-3 antagonist with an acceptable human safety profile that has been demonstrated to have an antimyeloma effect in the context of bortezomib resistance. In the present study, the mechanisms of action of GCS-100 are elucidated in myeloma cell lines and primary tumor cells. GCS-100 induced inhibition of proliferation, accumulation of cells in sub-G(1) and G(1) phases, and apoptosis with activation of both caspase-8 and -9 pathways. Dose- and time-dependent decreases in MCL-1 and BCL-X(L) levels also occurred, accompanied by a rapid induction of NOXA protein, whereas BCL-2, BAX, BAK, BIM, BAD, BID, and PUMA remained unchanged. The cell-cycle inhibitor p21(Cip1) was up-regulated by GCS-100, whereas the procycling proteins CYCLIN E2, CYCLIN D2, and CDK6 were all reduced. Reduction in signal transduction was associated with lower levels of activated IkappaBalpha, IkappaB kinase, and AKT as well as lack of IkappaBalpha and AKT activation after appropriate cytokine stimulation (insulin-like growth factor-1, tumor necrosis factor-alpha). Primary myeloma cells showed a direct reduction in proliferation and viability. These data demonstrate that the novel therapeutic molecule, GCS-100, is a potent modifier of myeloma cell biology targeting apoptosis, cell cycle, and intracellular signaling and has potential for myeloma therapy.
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PMID:GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. 2019 Jan 89

Noscapine, a benzylisoquinoline alkaloid derived from opium, was recently reported to exhibit activity against a variety of cancers through a poorly understood mechanism. Because the transcription factor NF-kappaB has been linked with inflammation, survival, proliferation, invasion, and angiogenesis in tumors, we hypothesized that noscapine mediates its effects by modulating the NF-kappaB activation pathway. We found that noscapine potentiates apoptosis induced by cytokines and chemotherapeutic agents in tumor cells. Noscapine alone suppressed proliferation of human leukemia and myeloma cells and downregulated the constitutive expression of cell survival proteins. Noscapine also abrogated the inducible expression of proteins involved in survival, proliferation, invasion, and angiogenesis, all of which are regulated by NF-kappaB. Noscapine suppressed both inducible and constitutive NF-kappaB activation in tumor cells through inhibition of IkappaB kinase, leading to inhibition of phosphorylation and degradation of IkappaBalpha. Noscapine also suppressed phosphorylation and nuclear translocation of p65, leading to inhibition of NF-kappaB reporter activity induced by various components of the NF-kappaB activation pathway. Activity of the NF-kappaB-containing cyclooxygenase-2 promoter was also inhibited by noscapine. Thus, noscapine inhibits the proliferation of leukemia cells and sensitizes them to tumor necrosis factor and chemotherapeutic agents by suppressing the NF-kappaB signaling pathway.
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PMID:Noscapine, a benzylisoquinoline alkaloid, sensitizes leukemic cells to chemotherapeutic agents and cytokines by modulating the NF-kappaB signaling pathway. 2035 90

Agents that are safe, affordable, and efficacious are urgently needed for the prevention of chronic diseases such as cancer. Sesamin, a lipid-soluble lignan, is one such agent that belongs to a class of phytoestrogens, isolated from sesame (Sesamum indicum), and has been linked with prevention of hyperlipidemia, hypertension, and carcinogenesis through an unknown mechanism. Because the transcription factor NF-kappaB has been associated with inflammation, carcinogenesis, tumor cell survival, proliferation, invasion, and angiogenesis of cancer, we postulated that sesamin might mediate its effect through the modulation of the NF-kappaB pathway. We found that sesamin inhibited the proliferation of a wide variety of tumor cells including leukemia, multiple myeloma, and cancers of the colon, prostate, breast, pancreas, and lung. Sesamin also potentiated tumor necrosis factor-alpha-induced apoptosis and this correlated with the suppression of gene products linked to cell survival (e.g., Bcl-2 and survivin), proliferation (e.g., cyclin D1), inflammation (e.g., cyclooxygenase-2), invasion (e.g., matrix metalloproteinase-9, intercellular adhesion molecule 1), and angiogenesis (e.g., vascular endothelial growth factor). Sesamin downregulated constitutive and inducible NF-kappaB activation induced by various inflammatory stimuli and carcinogens, and inhibited the degradation of IkappaBalpha, the inhibitor of NF-kappaB, through the suppression of phosphorylation of IkappaBalpha and inhibition of activation of IkappaBalpha protein kinase, thus resulting in the suppression of p65 phosphorylation and nuclear translocation, and NF-kappaB-mediated reporter gene transcription. The inhibition of IkappaBalpha protein kinase activation was found to be mediated through the inhibition of TAK1 kinase. Overall, our results showed that sesamin may have potential against cancer and other chronic diseases through the suppression of a pathway linked to the NF-kappaB signaling.
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PMID:Sesamin manifests chemopreventive effects through the suppression of NF-kappa B-regulated cell survival, proliferation, invasion, and angiogenic gene products. 2046 Apr 1


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