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)

When a replicative DNA polymerase encounters a lesion on the template strand and stalls, it is replaced with another polymerase(s) with low processivity that bypasses the lesion to continue DNA synthesis. This phenomenon is known as translesion replication or replicative bypass. Failing this, the cell is increasingly likely to undergo apoptosis. In this study, we found that proteasome inhibitors prevent translesion replication in human cancer cells but not in normal cells. Three proteasome inhibitors, MG-132, lactacystin, and MG-262, inhibited UV-induced translesion replication in a wide range of cancer cell lines, including HeLa, HGC-27, MCF-7, HepG2, WiDr, a malignant melanoma, an acute lymphoblastic leukemia, and a multiple myeloma cell line; irrespective of cell origin, histological type, or p53 status. In contrast, these inhibitors had little or no influence on normal fibroblasts (NB1RGB and TIG-1) or a normal liver mesenchymal (LI90) cell line. Among the DNA-damaging antineoplastic agents, cisplatin caused a UV-type translesion reaction; the proteasome inhibitors delayed cisplatin-induced translesion replication in cancer cell lines but had only a weak effect on normal cell lines. Therefore, translesion replication would be an effective target of proteasome inhibitors for cancer chemotherapy by which cancer cells can be efficiently sensitized to DNA-damaging antineoplastic agents, such as cisplatin.
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PMID:Proteasome inhibitors remarkably prevent translesion replication in cancer cells but not normal cells. 1829 77

Twelve steroidal platinum(II) complexes were synthesized by reaction of potassium tetrachloroplatinate with steroidal esters of L-methionine and L-histidine. The steroidal esters coordinated as bidentate ligands via S and N donor atoms of L-methionine and via two N donor atoms of L-histidine. Cholesterol, cholestanol, diosgenine, pregnenolone, dehydroepiandrosterone, testosterone, estrone, and estradiol were used as the steroidal compounds. The esters and complexes prepared were characterized by infrared, mass, and (1)H NMR spectroscopy and elemental analysis. Platinum complexes were tested for in vitro cytotoxicity against several cancer cell lines: T-lymphoblastic leukemia CEM, breast carcinoma MCF-7, lung carcinoma A-549, multiple myeloma RPMI 8226, and one normal cell line human fibroblast BJ.
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PMID:Platinum(II) complexes with steroidal esters of L-methionine and L-histidine: synthesis, characterization and cytotoxic activity. 1829 92

Steroid hormone receptors, like glucocorticoid (GR) and estrogen receptors (ER), are master regulators of genes that control many biological processes implicated in health and disease. Gene expression is dependent on receptor levels which are tightly regulated by the ubiquitin-proteasome system. Previous studies have shown that proteasome inhibition increases GR, but decreases ER-mediated gene expression. At the gene expression level this divergent role of the proteasome in receptor-dependent transcriptional regulation is not well understood. We have used a genomic approach to examine the impact of proteasome activity on GR- and ER-mediated gene expression in MCF-7 breast cancer cells treated with dexamethasone (DEX) or 17beta-estradiol (E2), the proteasome inhibitor MG132 (MG) or MG132 and either hormone (MD or ME2) for 24 h. Transcript profiling reveals that inhibiting proteasome activity modulates gene expression by GR and ER in a similar manner in that several GR and ER target genes are upregulated and downregulated after proteasome inhibition. In addition, proteasome inhibition modulates receptor-dependent genes involved in the etiology of a number of human pathological states, including multiple myeloma, leukemia, breast/prostate cancer, HIV/AIDS, and neurodegenerative disorders. Importantly, our analysis reveals that a number of transcripts encoding histone and DNA modifying enzymes, prominently histone/DNA methyltransferases and demethylases, are altered after proteasome inhibition. As proteasome inhibitors are currently in clinical trials as therapy for multiple myeloma, HIV/AIDS and leukemia, the possibility that some of the target molecules are hormone regulated and chromatin modifying enzymes is intriguing in this era of epigenetic therapy.
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PMID:Genome wide transcriptional profiling in breast cancer cells reveals distinct changes in hormone receptor target genes and chromatin modifying enzymes after proteasome inhibition. 1838 91

Bisphosphonates (BPs) are effective inhibitors of tumor-induced bone resorption. Recent studies have demonstrated that BPs inhibit growth, attachment and invasion of cancer cells in culture and promote apoptosis. The mechanisms responsible for the observed anti-tumor effects of BPs are beginning to be elucidated. Recently, we reported that nitrogen-containing bisphosphonates (N-BPs) induce formation of a novel ATP analog (ApppI) as a consequence of the inhibition of farnesyl diphosphate synthase in the mevalonate pathway. Similar to AppCp-type metabolites of non-N-BPs, ApppI is able to induce apoptosis. This study investigated BP-induced ATP analog formation and its effect on cancer cell growth. To evaluate zoledronic acid (a N-BP)-induced ApppI accumulation, inhibition of protein prenylation and clodronate (a non-N-BP) metabolism to AppCCl2p, MCF-7 and MDA-MB-436 breast cancer cells, MCF-10A nonmalignant breast cells, PC-3 prostate cancer cells, MG-63 osteosarcoma cells, RPMI-8226, and NCI-H929 myeloma cells were treated with 25 micromol/l zoledronic acid or 500 micromol/l clodronate for 24 h. The inhibition of cell growth by zoledronic acid and clodronate was studied in MCF-7, MDA-MB-436, and RPMI-8226 cells by exposing the cells with 1-100 micromol/l zoledronic acid or 10-2000 micromol/l clodronate for 72 h. Marked differences in zoledronic acid-induced ApppI formation and clodronate metabolism between the cancer cell lines were observed. The production of cytotoxic ATP analogs in tumor cells after BP treatment is likely to depend on the activity of enzymes, such as farnesyl diphosphate synthase or aminoacyl-tRNA synthetases, responsible for ATP analog formation. Additionally, the potency of clodronate to inhibit cancer cell growth corresponds to ATP analog formation.
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PMID:Bisphosphonate-induced ATP analog formation and its effect on inhibition of cancer cell growth. 1845 49

Allylic hydroxylated derivatives of the C18 unsaturated fatty acids were prepared from linoleic acid (LA) and conjugated linoleic acids (CLAs). The reaction of LA methyl ester with selenium dioxide (SeO(2)) gave mono-hydroxylated derivatives, 13-hydroxy-9Z,11E-octadecadienoic acid, 13-hydroxy-9E,11E-octadecadienoic acid, 9-hydroxy-10E,12Z-octadecadienoic acid and 9-hydroxy-10E,12E-octadecadienoic acid methyl esters. In contrast, the reaction of CLA methyl ester with SeO(2) gave di-hydroxylated derivatives as novel products including, erythro-12,13-dihydroxy-10E-octadecenoic acid, erythro-11,12-dihydroxy-9E-octadecenoic acid, erythro-10,11-dihydroxy-12E-octadecenoic acid and erythro-9,10-dihydroxy-11E-octadecenoic acid methyl esters. These products were purified by normal-phase short column vacuum chromatography followed by high-performance liquid chromatography (HPLC). Their chemical structures were characterized by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance spectroscopy (NMR). The allylic hydroxylated derivatives of LA and CLA exhibited moderate in vitro cytotoxicity against a panel of human cancer cell lines including chronic myelogenous leukemia K562, myeloma RPMI8226, hepatocellular carcinoma HepG2 and breast adenocarcinoma MCF-7 cells (IC(50) 10-75 microM). The allylic hydroxylated derivatives of LA and CLA also showed toxicity to brine shrimp with LD(50) values in the range of 2.30-13.8 microM. However these compounds showed insignificant toxicity to honeybee at doses up to 100 microg/bee.
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PMID:Synthesis and biological activity of hydroxylated derivatives of linoleic acid and conjugated linoleic acids. 1914 41

Numerous proteins controlling cell cycle progression, apoptosis and angiogenesis are degraded by the ubiquitin/proteasome system, which has become the subject for intense investigations for cancer therapeutics. Therefore, we used in silico and experimental approaches to screen compounds from the NCI chemical libraries for inhibitors against the chymotrypsin-like (CT-L) activity of the proteasome and discovered PI-083. Molecular docking indicates that PI-083 interacts with the Thr21, Gly47 and Ala49 residues of the beta5 subunit and Asp114 of the beta6 subunit of the proteasome. PI-083 inhibits CT-L activity and cell proliferation and induces apoptosis selectively in cancer cells (ovarian T80-Hras, pancreatic C7-Kras and breast MCF-7) as compared to their normal/immortalized counterparts (T80, C7 and MCF-10A, respectively). In contrast, Bortezomib, the only proteasome inhibitor approved by the Food and Drug Administration (FDA), did not exhibit this selectivity for cancer over non-transformed cells. In addition, in all cancer cells tested, including Multiple Myeloma (MM), breast, pancreatic, ovarian, lung, prostate cancer cell lines as well as fresh MM cells from patients, PI-083 required less time than Bortezomib to induce its antitumor effects. Furthermore, in nude mouse xenografts in vivo, PI-083, but not Bortezomib, suppressed the growth of human breast and lung tumors. Finally, following in vivo treatment of mice, PI-083 inhibited tumor, but not hepatic liver CT-L activity, whereas Bortezomib inhibited both tumor and liver CT-L activities. These results suggest that PI-083 is more selective for cancer cells and may have broader antitumor activity and therefore warrants further advanced preclinical studies.
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PMID:Discovery of a novel proteasome inhibitor selective for cancer cells over non-transformed cells. 1977 May 79

Arsenic trioxide (As(2)O(3)) is a frontline drug for treatment of acute promyelocytic leukemia and is in clinical trials for treatment of other malignancies, including multiple myeloma; however, efforts to expand clinical utility to solid tumors have been limited by toxicity. Nanoparticulate forms of As(2)O(3) encapsulated in 100-nm-scale, folate-targeted liposomes have been developed to lower systematic toxicity and provide a platform for targeting this agent. The resultant arsenic "nanobins" are stable under physiologic conditions but undergo triggered drug release when the pH is lowered to endosomal/lysosomal levels. Cellular uptake and antitumor efficacy of these arsenic liposomes have been evaluated in folate receptor (FR)-positive human nasopharyngeal (KB) and cervix (HeLa) cells, as well as FR-negative human breast (MCF-7) tumor cells through confocal microscopy, inductively coupled plasma mass spectroscopy, and cytotoxicity studies. Uptake of folate-targeted liposomal arsenic by KB cells was three to six times higher than that of free As(2)O(3) or nontargeted liposomal arsenic; the enhanced uptake occurs through folate-mediated endocytosis, leading to a 28-fold increase in cytotoxicity. In contrast, tumor cells with lower FR density on the surface (HeLa and MCF-7) showed much less uptake of the folate-targeted drug and lower efficacy. In cocultures of KB and MCF-7 cells, the folate-targeted arsenic liposomes were exclusively internalized by KB cells, showing high targeting specificity. Our studies further indicate that folate-targeted delivery of As(2)O(3) with coencapsulated nickel(II) ions (as a nontoxic adjuvant) potentiates the As(2)O(3) efficacy in relatively insensitive solid tumor-derived cells and holds the promise of improving drug therapeutic index.
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PMID:Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide. 1956 24

Four new n-butylamino and two sulfur-containing derivatives of polyfluoro-1,4-naphthoquinone were synthesized and their mutagenic and antioxidant properties in Salmonella cells, as well as the cytotoxicity in human myeloma (RPMI 8226), human mammary adenocarcinoma (MCF-7), mouse fibroblasts (LMTK) and primary mouse fibroblast cells (PMF) were studied. 2-n-Butylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1) showed efficient inhibition of the growth of the tumor cells. 2,8-Di-(n-butyl-amino)-3,5,6,7-tetrafluoro-1,4-naphthoquinone (2) had significantly less growth-inhibiting properties, while 2,6-di-(n-butylamino)-3,5,7,8-tetrafluoro-1,4-naphthoquinone (3) and 2,6,8-tri-(n-butylamino)-3,5,7-tetrafluoro-1,4-naphthoquinone (4), demonstrated very low cytotoxicity. Compounds 1 and 2 were remarkably less cytotoxic while compound 3 and 4 were not cytotoxic toward LMTK and PMF cells as compared with tumor human cell lines. Cytotoxicity of 2-(2'-methylthioethyl)amino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (5) and (2,2'-dithiodi-2)-3,5,6,7,8-pentafluoro-1,4-naphthoquinone-2-ylamino)ethan (6) toward mammalian cells was compared with that for compounds 1 and 2.
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PMID:Cytotoxicity of new n-butylamino and sulfur-containing derivatives of polyfluorinated 1,4-naphthoquinone. 1988 55

Fluorinated derivatives of 1,4-naphthoquinone are highly potent inhibitors of Cdc25A and Cdc25 phosphatases and growth of tumor cells. Five new N-substituted polyfluorinated derivatives of 2-amino-1,4-naphthoquinone were synthesized and their mutagenic and antioxidant properties in Salmonella cells, as well as cytotoxicity in human myeloma (RPMI 8226), human mammary adenocarcinoma (MCF-7), mouse fibroblasts (LMTK) and primary mouse fibroblast cells (PMF) were studied. 2-tert-Butylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1) inhibited the growth of normal control and tumor cells at the same concentration. Three compounds: 2-diethylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (2), 2-ethylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (3), 2-phenylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (4) exhibited a 50% decrease in the growth of cancer cells at low and comparable concentrations (2.4-8.6 microM) while being remarkably less cytotoxic toward normal LMTK and PMF cells. Quinones (1)-(4), but not 2-phenylamino-3-methyl-5,6,7,8-tetrafluoro-1,4-naphthoquinone (5), efficiently suppressed spontaneous mutagenesis in Salmonella cells, while all compounds 1-5 decreased the mutagenic effect of H2O2 on bacterial cells. Their possible perspectives as anticancer drugs are shortly discussed.
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PMID:Cytotoxicity of new alkylamino- and phenylamino-containing polyfluorinated derivatives of 1,4-naphthoquinone. 2018 92

Mammalian alpha4 phosphoprotein, the homolog of yeast Tap42, is a component of the mammalian target-of-rapamycin (mTOR) pathway that regulates ribogenesis, the initiation of translation, and cell-cycle progression. alpha4 is known to interact with the catalytic subunit of protein phosphatase 2A (PP2Ac) and to regulate PP2A activity. Using alpha4 as bait in yeast two-hybrid screening of a human K562 erythroleukemia cDNA library, EDD (E3 isolated by differential display) E3 ubiquitin ligase was identified as a new protein partner of alpha4. EDD is the mammalian ortholog of Drosophila hyperplastic discs gene (hyd) that controls cell proliferation during development. The EDD protein contains a PABC domain that is present in poly(A)-binding protein (PABP), suggesting that PABP may also interact with alpha4. PABP recruits translation factors to the poly(A)-tails of mRNAs. In the present study, immunoprecipitation/immunoblotting (IP/IB) analyses showed a physical interaction between alpha4 and EDD in rat Nb2 T-lymphoma and human MCF-7 breast cancer cell lines. alpha4 also interacted with PABP in Nb2, MCF-7 and the human Jurkat T-leukemic and K562 myeloma cell lines. COS-1 cells, transfected with Flag-tagged-pSG5-EDD, gave a (Flag)-EDD-alpha4 immunocomplex. Furthermore, deletion mutants of alpha4 were constructed to determine the binding site for EDD. IP/IB analysis showed that EDD bound to the C-terminal region of alpha4, independent of the alpha4-PP2Ac binding site. Therefore, in addition to PP2Ac, alpha4 interacts with EDD and PABP, suggesting its involvement in multiple steps in the mTOR pathway that leads to translation initiation and cell-cycle progression.
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PMID:alpha4 phosphoprotein interacts with EDD E3 ubiquitin ligase and poly(A)-binding protein. 2054 96


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