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

A search for new agents that can sensitise cancer cells to ionising radiation is of continual interest and mainly due to the use of radiation in cancer therapy. Resveratrol, a powerful antioxidant has been shown to inhibit carcinogenesis in animal models. The purpose of this study was to examine whether resveratrol can sensitise cancer cells to X-irradiation. The human cancer cell lines examined were HELA (cervix carcinoma), K-562 (chronic myeloid leukemia) and IM-9 (multiple myeloma). The assays that were performed following X-irradiation (doses from 0 to 8 Gy) and/or incubation in the presence of resveratrol (concentrations ranging from 0 to 200 microM), were the following: trypan blue exclusion test to determine cell viability, cell morphology after May-Grunwald Giemsa staining, DNA profile analysis by flow cytometry to assess cell cycle distribution and the presence of the sub-G1 peak. The cell lines showed different radiation sensitivity (IM-9, high radiation sensitivity, K-562, intermediate radiation sensitivity and HELA, low radiation sensitivity) as seen by the X-irradiation dose related inhibition of cell growth and induction of apoptosis. The addition of resveratrol alone to the cell cultures induced apoptosis and inhibited cell growth from 50 (IM-9), 100 (EOL-1) or 200 microM (HELA) resveratrol concentrations. Concomitant treatment of the cells with either resveratrol and X-irradiation induced a synergical effect at the highest dose of 200 microM. These results show that resveratrol can act as a potential radiation sensitiser at high concentrations. Further studies need to address the toxicity of resveratrol on normal cells.
 ...
PMID:Enhanced radiation-induced apoptosis of cancer cell lines after treatment with resveratrol. 1513 32

Genetic instability is a prominent feature in multiple myeloma and progression of this disease from monoclonal gammopathy of uncertain significance (MGUS) and smouldering myeloma (SMM) is associated with increasing molecular and chromosomal abnormalities. The DNA mismatch repair (MMR) pathway is a post-replicational DNA repair system that maintains genetic stability by repairing mismatched bases and insertion/deletion loops mistakenly incorporated during DNA replication. Deficiencies in proteins pivotal to this pathway result in a higher mutation rate, particularly at regions of microsatellite DNA. We have investigated the proficiency of the MMR pathway in clinical samples and myeloma cell lines. Microsatellite analysis showed instability at one or more of nine loci examined in 15 from 92 patients: 7.7% of MGUS/SMM, 20.7% of MM/plasma cell leukaemia (PCL) and 12.5% of relapsed MM/PCL. An in vitro heteroduplex G/T repair assay found reduced repair in two cell lines, JIM1 and JIM3, and in two of four PCL cases and was associated with aberrant expression of at least one mismatch repair protein. Thus we show that MMR defects are found in plasma cell dyscrasias and the increased frequency during more active stages of the disease suggests a contributory role in disease progression.
Carcinogenesis 2004 Oct
PMID:DNA mismatch repair pathway defects in the pathogenesis and evolution of myeloma. 1514 87

The epigenetic control of gene transcription in cancer has been the theme of many recent studies and therapeutic approaches. Carcinogenesis is frequently associated with hypermethylation and consequent down-regulation of genes that prevent cancer, e.g., those that control cell proliferation and apoptosis. We used the demethylating drug zebularine to induce changes in DNA methylation, then examined patterns of gene expression using cDNA array analysis and Restriction Landmark Genomic Scanning followed by RNase protection assay and reverse transcription-PCR to confirm the results. Microarray studies revealed that many genes were epigenetically regulated by methylation. We concluded that methylation decreased the expression of, or silenced, several genes, contributing to the growth and survival of multiple myeloma cells. For example, a number of genes (BAD, BAK, BIK, and BAX) involved in apoptosis were found to be suppressed by methylation. Sequenced methylation-regulated DNA fragments identified by Restriction Landmark Genomic Scanning were found to contain CpG islands, and some corresponded to promoters of genes that were regulated by methylation. We also observed that after the removal of the demethylating drug, the addition of interleukin 6 restored CpG methylation and re-established previously silenced gene patterns, thus implicating a novel role of interleukin 6 in processes regulating epigenetic gene repression and carcinogenesis.
 ...
PMID:Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line. 1515 99

Lung cancer is the leading cause of cancer-related death in developed countries. Non-small cell lung cancer (NSCLC) represents 80% of the total lung cancer cases and is comprised of adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma and large cell carcinoma (LCC) subtypes. The ability of LCC to metastasize earlier than the other forms of lung cancer suggests anti-angiogenic drugs as effective agents to combat this cancer. Thalidomide is an anti-angiogenic drug that has shown promise in multiple hematological diseases, and myeloma and other cancers. However, the molecular mechanism by which thalidomide exerts its effects is poorly understood. Therefore, we evaluated the effectiveness of thalidomide on NSCLC cell growth, and found that LCC cells were growth inhibited by 40-60%. This effect seemed specific to LCC cancer cells, since other forms of NSCLC were only mildly affected by thalidomide. At the molecular level, thalidomide increased peroxisome proliferator-activated receptor gamma (PPARgamma) protein dose-dependently, and peroxisome proliferator response element activity. Further, thalidomide treatment of LCC cells decreased nuclear factor kappa B activity in a dose-dependent fashion, increased apoptosis and decreased the expression of angiogenic proteins. In our mouse xenograft model of lung cancer, we found that intratumoral thalidomide caused a 64% decrease in tumor growth; moreover, tumors from the thalidomide-treated mice expressed higher PPARgamma, than tumors from control mice. This study shows the antitumor activity of thalidomide against LCC tumors and suggests a model in which thalidomide exerts its antitumor effects on LCC cells through the induction of PPARgamma and subsequent downstream signaling. To our knowledge, this is the first study to show a link between thalidomide and PPARgamma.
Carcinogenesis 2004 Oct
PMID:The effect of thalidomide on non-small cell lung cancer (NSCLC) cell lines: possible involvement in the PPARgamma pathway. 1520 58

The interleukin-mediated Janus kinase (JAK)/STAT pathway plays a crucial role in carcinogenesis. Recently, increased STAT3 activity was found in hepatocellular carcinoma and multiple myeloma in which there was silencing of SOCS-1 (suppressor of cytokine signalling-1) by gene promoter hypermethylation. We investigated the expression level of interleukin-6 (IL-6) and SOCS-1 in gastric cancer cell lines. Expression of SOCS-1 correlated with IL-6 level in most of the cell lines, except for AGS cells in which SOCS-1 was absent despite a high level of IL-6 production. Methylation analysis by methylation-specific polymerase chain reaction and bisulphite sequencing revealed that CpG island of SOCS-1 was densely methylated in AGS cells. Demethylation treatment by 5'aza-deoxycytidine restored SOCS-1 expression and also suppressed constitutive STAT3 phosphorylation in AGS cells. Moreover, methylation of SOCS-1 was detected in 27.5% (11 of 40) of primary gastric tumours samples, 10% (one of 10) of adjacent noncancer tissues but not in any (zero of nine) normal gastric mucosa. Methylation of SOCS-1 also correlated with the loss of mRNA expression in some primary gastric cancers. In conclusion, this is the first report to demonstrate that hypermethylation of SOCS-1 led to gene silencing in gastric cancer cell line and primary tumour samples. Downregulation of SOCS-1 cooperates with IL-6 in the activation of JAK/STAT pathway in gastric cancer.
 ...
PMID:Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line. 1535 12

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
 ...
PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

In our previous studies, DAZAP2 gene expression was down-regulated in untreated patients of multiple myeloma (MM). For better studying the structure and function of DAZAP2, a full-length cDNA was isolated from mononuclear cells of a normal human bone marrow, sequenced and deposited to Genbank (AY430097). This sequence has an identical ORF (open reading frame) as the NM_014764 from human testis and the D31767 from human cell line KG-1. Phylogenetic analysis and structure prediction reveal that DAZAP2 homologues are highly conserved throughout evolution and share a polyproline region and several potential SH2/SH3 binding sites. DAZAP2 occurs as a single-copy gene with a four-exon organization. We further noticed that the functional DAZAP2 gene is located on Chromosome 12 and its pseudogene gene is on Chromosome 2 with electronic location of human chromosome in Genbank, though no genetic abnormalities of MM have been reported on Chromosome 12. The ORF of human DAZAP2 encodes a 17-kDa protein, which is highly similar to mouse Prtb. The DAZAP2 protein is mainly localized in cytoplasm with a discrete pattern of punctuated distribution. DAZAP2 may associate with carcinogenesis of MM and participate in yet-to-be identified signaling pathways to regulate proliferation and differentiation of plasma cells.
 ...
PMID:The structure, expression and function prediction of DAZAP2, a down-regulated gene in multiple myeloma. 1562 43

There are a number of reports on collision occurrence of non-hematologic cancers and Non-Hodgkin's lymphoma (NHL) and multiple myeloma. In this report we present a case of patient with immunoproliferative disease, extramedullary plasmocytoma and NHL-lymphoplasmocytoid lymphoma (LPL) and squamous cell carcinoma of the lung. After diagnosis of extramedullary plasmocytoma cytostatic therapy was commenced and the patient was well. Five years after patient was clinically worse and diagnostic evaluation this time revealed lymphoplasmocytoid cells in bone marrow. Five months later malignant morphologically undifferentiated cells were found in bone marrow which were by immunocytochemistry established as CD38 positive. After the patient's death, disseminated NHL-LPL and squamous cell carcinoma of lung was confirmed. In the report, we compared clinical course and diagnostic findings of our patient with literature data. We have also discussed the possible relationship of multiple B-cell lymphoid tumors and squamous cell carcinoma concluding that multidiscplinary diagnostic tools are essential not only for carcinoma diagnosis and follow-up, but also for further understanding of carcinogenesis.
 ...
PMID:Patient with immunoproliferative disease and lung carcinoma: a case report. 1563 71

Although statins are lipid-lowering drugs that block cholesterol biosynthesis, they exert immunomodulatory, anti-inflammatory, anti-angiogenic and anti-proliferative functions by reducing the isoprenylation of proteins involved in cell signal transduction such as Ras and RhoA. In this study, we provide evidence that several natural (lovastatin, simvastatin and pravastatin) and synthetic (cerivastatin and atorvastatin) statins exert a cytotoxic effect on human T, B and myeloma tumor cells by promoting their apoptosis. Dissimilar susceptibility to apoptosis has been detected in these lines, presumably in relation to the altered expression of proteins involved in the regulation of cellular signals. Cerivastatin promptly activated the cell death even in doxorubicin resistant cell lines such as MCC-2, whereas pravastatin, a hydrophilic compound, failed to induce any effect on either proliferation or apoptosis. The statin-induced apoptotic pathway in these cell lines was presumably regulated by altered prenylation of either Ras or RhoA, as measured by the defective membrane localization of these small GTPases. In addition the cell proliferation was rescued by both farnesylpyrophosphate (FPP) and geranyl-geranylpyrophosphate (GGPP), whereas no effect was obtained with squalene, a direct precursor of cholesterol. Statins primed apoptosis through its intrinsic pathway involving the mitochondria. In fact, we observed the reduction of mitochondrial membrane potential and the cytosolic release of the second mitochondria-derived activator of caspases (Smac/DIABLO). The apoptotic pathway was caspase-dependent since caspases 9, 3 and 8 were efficiently activated. These results support the potential use of statins in association with conventional treatment as apoptosis-triggering agents in these tumors.
Carcinogenesis 2005 May
PMID:Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. 1570 2

Multiple myeloma (MM) cell interactions with their microenvironment modulate acquired drug resistance and disease progression. Indeed, reported aberrant gene methylation underscores the possible role of epigenetic events in MM's molecular profile. Membranal tetraspanins are often inversely correlated with cancer prognosis and metastasis, however mutations were unidentified hitherto. Their promoter characteristics and frequent down-regulation conform to transcriptional silencing by chromatin remodeling. We delineated the baseline expression of select tetraspanins in MM cell lines (RPMI 8226, U266, ARP1, ARK, CAG and EBV transformed ARH77) and fresh bone marrow samples (n = 9) for the first time and determined reduced expression of CD9, CD81 and absence of CD82. Thus, we aimed to assess their promoter methylation status. Indeed, we established CD9, CD81 and CD82 promoter methylation in MM cell lines employing methyl-specific-PCR of bisulfite modified G-DNA and PCR of G-DNA digested with methylation-sensitive restriction enzyme (Hin6I). Re-transcription of assayed genes in the cell lines following de-methylation [5-aza-2'-deoxycytidine (5-aza-dC)] confirmed the mechanistic significance of methylation to their regulation. Combined de-methylation and de-acetylation [Trichostatin A (TsA)] induced synergistic elevation of CD82 mRNA. We conclude that chromatin remodeling contributes to tetraspanin silencing in MM.
Carcinogenesis 2006 Feb
PMID:Promoter hypermethylation of tetraspanin members contributes to their silencing in myeloma cell lines. 1611 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>