Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lovastatin blocks the biosynthesis of the isoprenoid precursor, mevalonate. When Friend murine erythroleukemia (MEL) cells are cultured in medium containing lovastatin, the precursor of murine leukemia virus envelope glycoprotein (gPr90env) fails to undergo proteolytic processing, which normally occurs in the Golgi complex. Consequently, newly synthesized envelope proteins are not incorporated into viral particles that are shed into the culture medium. gPr90env appears to be localized in a pre-Golgi membrane compartment, based on its enrichment in subcellular fractions containing NADPH-cytochrome c reductase activity and the sensitivity of its carbohydrate chains to digestion with endoglycosidase H. Arrest of gPr90env processing occurs at concentrations of lovastatin that are not cytostatic, and the effect of the inhibitor is prevented by addition of mevalonate to the medium. The low molecular mass GTP-binding proteins, rab1p and rab6p, which are believed to function in early steps of the exocytic pathway, are normally modified posttranslationally by geranylgeranyl isoprenoids. However, in MEL cells treated with 1 microM lovastatin, nonisoprenylated forms of these proteins accumulate in the cytosol prior to arrest of gPr90env processing. These observations suggest that lovastatin may prevent viral envelope precursors from reaching the Golgi compartment by blocking the isoprenylation of rab proteins required for ER to Golgi transport.
 ...
PMID:Isoprenoid requirement for intracellular transport and processing of murine leukemia virus envelope protein. 142 16

We assessed the antiproliferative effect of tumor necrosis factor alpha (TNF-alpha) and lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, alone and in combination, on two murine tumor cell lines. Recombinant TNF-alpha inhibited proliferation of murine MmB16 melanoma cells in a concentration-dependent fashion but stimulated growth of murine L1210 leukemia cells at 0.1 ng/ml concentration. Lovastatin inhibited proliferation both of murine MmB16 melanoma cells and of murine L1210 leukemia cells in a concentration-dependent fashion. In combination with tumor necrosis factor alpha lovastatin inhibited synergistically growth of both cell lines as assessed by isobologram analysis. Our data show that lovastatin, a cholesterol synthesis inhibitor, introduced to the clinic to treat hypercholesterolemia, used either as a single or in combination with TNF-alpha inhibits growth of MmB16 melanoma and L1210 leukemia cells.
 ...
PMID:Synergistic antiproliferative activity of tumor necrosis factor alpha (TNF-alpha) and lovastatin. 748 65

This study has determined the effects of phorbol-12-myristate-13-acetate (PMA) and dimethylsulfoxide (DMSO) on mRNA levels for the serglycin proteoglycan core protein in human erythroleukemia (HEL) cells. We have compared these changes to those for mRNA for other proteins which are known to be synthesized by HEL cells and megakaryocytes and are known to be localized to alpha granules within platelets. PMA caused a large increase in mRNA for serglycin within two hours of treatment of the cells, and the increase persisted for at least 72 hours. DMSO did not cause a significant change in mRNA levels. mRNA for platelet factor 4, transforming growth factor-beta, and P-Selectin (PADGEM, GMP-140) were also increased by PMA treatment. The mRNA for platelet factor 4 was substantially reduced in the presence of DMSO. The increase of mRNA for serglycin induced by PMA was consistent with our previous observation that synthesis of proteoglycans from [35S]sulfate was greatly stimulated by PMA in HEL cells. The data suggest that up-regulation of synthesis of proteoglycans is induced by PMA in cells which have the capacity to differentiate along the megakaryocytic lineage, as opposed to cell lines such as HL-60 in which proteoglycan synthesis is reduced in the presence of this differentiation-inducing agent.
Leukemia 1993 Dec
PMID:Expression of mRNA for serglycin core protein and other platelet alpha granule proteins is increased in human erythroleukemia cells by phorbol myristate acetate. 750 70

Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, and 6-fluoromevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase, blocked the synthesis of downstream mevalonate products, including prenyl-derived lipids, and prevented membrane localization of Ras in the myeloid cell line U-937. In contrast to lovastatin, which induced cytosol localization of Ras in U-937 cells, Fmev failed to increase cytosolic Ras and also completely prevented the proliferation of U-937 cells. Growth of U-937 cells was restored by the addition of lovastatin to Fmev-blocked cells. These results implied that a product of mevalonate metabolism proximal to isopentenyl diphosphate was responsible for the suppression of proliferation. To delineate the action of this endogenous inhibitor of cell proliferation and determine the relationship between its impact on Ras localization and cell proliferation, the effect of Fmev on a variety of leukemia- and lymphoma-derived cells was examined. Whereas Fmev blocked the growth of these cell lines, there were more than 50-fold differences in the concentrations required to inhibit the growth of individual cell lines by 90%. Regardless of its effect on cell proliferation, the biochemical effect of Fmev was similar. Thus, Fmev uniformly prevented the conversion of radiolabeled mevalonate to isopentenyl diphosphate and other downstream products, including synthesis of sterol and nonsterol lipids and prenylation of proteins. A correlation was noted between higher intrinsic rates of mevalonate synthesis by a cell and susceptibility to inhibition by Fmev. Thus, sensitivity of a cell line to inhibition by Fmev was associated with markedly increased rates of HMG CoA reductase activity that were further increased by incubation with Fmev. Whereas Fmev depleted cellular levels of the prenylated protein Ras in the sensitive cell line U-937, there was no depletion of cellular Ras levels in the resistant cell line EL-4, but rather, there was a shift of Ras from membrane to cytosol, as expected for inhibition of prenylation. These results suggest that leukemic cells with increased HMG CoA reductase activity produce increased levels of an endogenous mevalonate-derived inhibitor that leads to Ras depletion and suppression of cell growth. As a result, inhibition of the growth of these transformed cells might be specifically accomplished by Fmev.
 ...
PMID:Regulation of proliferation and Ras localization in transformed cells by products of mevalonate metabolism. 927 19

Mevalonate pathway inhibitor lovastatin inhibited proliferation of human multidrug-resistant promyelocytic leukemia HL-60/ADR cells in vitro, with MRP-gene coded p190 mediated drug resistance, to a markedly lesser extent than that of the parental drug sensitive HL-60 cells and also that of the other human multidrug resistant (MDR-1, P-glycoprotein) myeloid leukemia cell line HL-60/VCR. The sensitivity of the examined human leukemia cell lines to the cytostatic activity of lovastatin correlated approximately with the potential of lovastatin to induce the characteristic cell cycle alteration (i.e. the accumulation of lovastatin-treated cells in the G0/G1 phase of the cell cycle). The P-glycoprotein positive HL-60/VCR cells and the parental drug sensitive HL-60 cells were more sensitive to this cell cycle alteration than the HL-60/ADR multidrug resistant leukemia cells with MRP drug resistance. Lovastatin (72 hours, 20 micromol) induced apoptosis and cell necrosis in HL-60 cells, apoptosis but not cell necrosis in HL-60/VCR cells and neither apoptosis nor necrosis in HL-60/ADR cells.
 ...
PMID:Human multidrug-resistant (MRP,p190) myeloid leukemia HL-60/ADR cells in vitro: resistance to the mevalonate pathway inhibitor lovastatin. 960 9

Lovastatin, a competitive inhibitor of HMG-CoA reductase, reportedly inhibits proliferation and induces apoptosis of tumor cells with MDR-1 coded P-glycoprotein (Pgp) expression. In this study we investigated the sensitivity to lovastatin of eight myeloid leukemia cell lines: K562, NOMO-1, NB4 and its retinoic acid (RA) resistant subline NB4/RA, and their multidrug-resistant (MDR) sublines: K562/ADR, NOMO-1/ADR, NB4/MDR and NB4/RA/MDR. MTT and apoptosis assays revealed that K562/ADR, NOMO-1/ADR and NB4/RA/MDR were more sensitive to lovastatin than their parental cell lines, while NB4/MDR showed the same level of sensitivity as parental NB4 cells, which already were very sensitive to lovastatin. Significant elevation of transcript levels of HMG-CoA reductase was observed by semiquantitative RT-PCR analysis in more than three lovastatin-sensitive MDR sublines, but not in NB4/MDR compared with the parental cell lines. HMG-CoA reductase mRNA levels were up-regulated more than two-fold by the exposure to lovastatin in all of the parental non-Pgp-expressing cell lines. In NB4/MDR, HMG-CoA reductase mRNA level was elevated to a similar extent as in parental NB4, whereas in three other MDR sublines which showed preferential sensitivity to lovastatin, their HMG-CoA reductase mRNA levels were not significantly elevated after 24- and 48-h treatment with lovastatin. These results indicate a connection between drug resistance and regulation of the mevalonate pathway, and further strengthen the clinical possibility that drug resistant leukemias would be susceptible to treatment with lovastatin.
Leukemia 2000 Aug
PMID:Increased sensitivity of multidrug-resistant myeloid leukemia cell lines to lovastatin. 1094 41

Lovastatin reduces the isoprenylation of p21ras via suppression of mevalonic acid generation. Lovastatin has been shown to reduce tumor cell proliferation in a dose-dependent manner. Here, the potential of lovastatin for purging leukemia cells from bone marrow was investigated using the myeloblastic cell lines K562 and KG-1 as a model system, derived from an erythroleukemia and an acute myelogenous leukemia, respectively. Optimal purging conditions were determined using an MTT proliferation and a leukemia colony assay. Elimination of leukemia cells was time- and dose-dependent. Depletion of K562 was 2.5 logs for 100 microM of lovastatin at 72 h of incubation. Compared to another purging agent, 100 microg/ml mafosfamide had an activity comparable to 100 mM lovastatin. Interestingly, KG-1 acute myelogenous leukemia cells were even more sensitive to lovastatin than K562 cells. In clonogenic assays, 100 microM of lovastatin resulted in a 3- to 4-log reduction of K562 colonies. Lovastatin had a progressive effect on normal hematopoietic progenitor cells. At a concentration of 100 microM of lovastatin, CFU-GM colonies were reduced by 1-2 logs. In conclusion, a differential effect on leukemia and normal progenitor cells could be detected in a clonogenic assay. These results suggest that lovastatin deserves further study as an agent for ex vivo marrow purging.
 ...
PMID:Increased sensitivity of myeloid leukemia cell lines: potential of lovastatin as bone-marrow-purging agent. 1115 78

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme of the mevalonate pathway, the diverse array of end products of which are vital for a variety of cellular functions, including cholesterol synthesis and cell cycle progression. We showed previously that this enzyme holds a critical role in regulating tumor cell fate, including cell death, as its expression is down-regulated in response to retinoic acid, a potent anticancer therapeutic. Indeed, direct inhibition of HMG-CoA reductase with lovastatin, a competitive inhibitor of this enzyme, induced a pronounced apoptotic response in neuroblastoma and acute myeloid leukemic cells. We have now extended this work and evaluated a wide variety and large number of tumor-derived cell lines for their sensitivity to lovastatin-induced apoptosis. These cell lines were exposed to a wide range (0-100 microM) of lovastatin for 2 days and assayed for cell viability using the 3,4,5-dimethyl thiazlyl-2,2,5-diphenyltetrazolium bromide assay and the induction of apoptosis by flow cytometric and ultrastructural analyses. Lovastatin induced a pronounced apoptotic response in cells derived from juvenile monomyelocytic leukemia, pediatric solid malignancies (rhabdomyosarcoma and medulloblastoma), and squamous cell carcinoma of the cervix and of the head and neck. Interestingly, the subset of malignancies that are particularly sensitive to lovastatin-induced apoptosis correspond to those tumor subtypes that are sensitive to the biological and antiproliferative effects of retinoids in vitro. The nature of the biologically active form of lovastatin has been challenged recently as the growth-inhibitory effects of this drug were attributed to its prodrug lactone form that does not inhibit HMG-CoA reductase function. In this report, we demonstrate that the apoptotic properties of lovastatin are triggered by the open ring acid form that is a potent inhibitor of HMG-CoA reductase activity. Thus, we have identified a subset of tumors that are sensitive to lovastatin-induced apoptosis and show HMG-CoA reductase as a potential therapeutic target of these cancers.
 ...
PMID:Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications. 1120 4

1. Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P-glycoprotein (P-gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over-expresses the multi-drug resistance protein 1a/b (mdr1a/1b). 2. P-gp modulation was studied by a fluorimetric assay and confocal microscopy by means of R123 efflux and uptake experiments, respectively. 3. Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration-dependent manner. Lovastatin acid, simvastatin acid, fluvastatin and pravastatin did not show a significant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest affinities for P-gp and results were comparable for both methods. 4. In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition to fluorimetric assay is a sensitive tool to study P-gp affinity in drug screening that is especially useful for early phases of drug development.
 ...
PMID:HMG-CoA reductase inhibitors and P-glycoprotein modulation. 1125 Aug 68

Cytosine arabinoside (ara-C) is widely used for the treatment of leukemias and displays significant toxicities. Lovastatin, an HMG-CoA reductase inhibitor, is extensively used to treat hypercholesterolemia. To determine whether lovastatin could augment ara-C's activity we have examined their effects in the human erythroleukemia K562 cell line and the ara-C resistant ARAC8D cell line. A synergistic interaction between the two drugs was found. We have demonstrated that the interaction does not occur at the level of RAS but may involve lovastatin's effect of downregulating MAPK activity and preventing ara-C-induced MAPK activation. These studies represent the first description of a potentially beneficial interaction between lovastatin and ara-C that could be applied to the treatment of human leukemia.
 ...
PMID:Interaction of cytosine arabinoside and lovastatin in human leukemia cells. 1139 70


1 2 Next >>