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 look for new candidates for agents to use in maintenance therapy for myeloma patients, the growth inhibitory effects of a 3-hydroxy-3-mehtylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin), simvastatin, was analyzed using human myeloma cell lines. Several investigations have indicated growth reduction in certain lineages of cancer cells including one report on myeloma, and inhibitory effects of statins on GTPases and involving MAP-kinases. Most (12 out of 13) myeloma lines examined showed growth inhibition when cultured with various concentrations (1-30 microM) of simvastatin in a dose-dependent manner. Simvastatin in combination with other biological response modifiers such as ATRA or DEX had additional effects on growth. In addition, anti-oxides prevented the simvastatin-induced growth inhibition and apoptosis. Furthermore, myeloma cells treated with simvastatin clearly showed inactivation of various MAP-kinase pathways such as ERK1/2, MEK1/2, JNK, and p38. Based on these findings, statins may be suitable for clinical usage in maintenance therapy for myeloma patients.
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PMID:Effects of an HMG-CoA reductase inhibitor, simvastatin, on human myeloma cells. 1506 46

To explore the apoptotic effect of simvastatin on K562 cells through endoplasmic reticulum stress, morphological change of apoptotic cells was observed by Hoechst33258 fluorescent staining under fluorescent microscope. Apoptosis rate of cells was determined with annexinV-FITC/PI double staining by flow cytometry; Intracellular calcium concentration ([Ca2+]i) was measured by laser scanning confocal microscope (LSCM); The expression levels of glucose regulated protein 78 (GRP78) and calpain gene mRNA were determined by RT-PCR; The expression levels of caspase-3, -6, -7, -9, -12, calpain and GRP78 proteins were evaluated by Western blotting. In this study, K562 cells treated with simvastatin for 72 h exhibited typical morphological change of apoptosis cells. After 72 h exposed to 10, 20, 30 micromol x L(-1) simvastatin, the apoptotic rates of K562 cells were 12.41%, 19.08% and 23.41%, respectively. Simvastatin induced the increase of [Ca2+]i in K562 cells, fluorescent intensities were 43, 54, and 64, respectively. The expression levels of GRP78 and calpain gene mRNA were up-regulated. The cleavage and activation of caspase-3, -6, -7, -9, -12 and upregulation of GRP78 expression were determined by Western blotting. These findings suggest that endoplasmic reticulum is an important pathway of apoptosis in cells and participates simvastatin-induced apoptosis in K562 cells. It is implied that simvastatin may be suitable for clinical usage in the treatment of myeloma patients.
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PMID:[Simvastatin-induced apoptosis of K562 cells is mediated by endoplasmic reticulum stress]. 1866 98

Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, is a cholesterol-lowering drug that may play a role in bone metabolism through a mechanism that is not fully understood. Recently, receptor activator of NF-kappaB ligand (RANKL), a member of the TNF superfamily, has emerged as a major mediator of bone loss via activation of osteoclastogenesis. The latter is also associated with certain cancers such as multiple myeloma and breast cancer. Whether simvastatin can modulate RANKL-induced or cancer induced osteoclastogenesis was investigated. The effect of simvastatin on RANKL signaling and consequent osteoclastogenesis was investigated. RANKL induced NF-kappaB activation, whereas pretreatment with simvastatin completely suppressed such activation and correlated with suppression of RANKL-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation and IkappaBalpha degradation. Similarly, RANKL induced the differentiation of monocytic cells to osteoclasts, whereas simvastatin suppressed it. The inhibition was maximal when cells were exposed to both simvastatin and RANKL simultaneously and minimal when simvastatin was added 1 day after RANKL treatment. Simvastatin also inhibited the osteoclastogenesis induced by human breast cancer and by multiple myeloma cells. Together, our results indicate that simvastatin inhibits the RANKL-induced NF-kappaB activation pathway that leads to suppression of osteoclastogenesis induced by RANKL and by tumor cells, thereby suggesting its therapeutic potential in osteoporosis and in cancer-related bone loss.
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PMID:Simvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, suppresses osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand through modulation of NF-kappaB pathway. 1868 62