Growth inhibition and induction of phenotypic alterations in MCF-7 breast cancer cells by an IMP dehydrogenase inhibitor

Sidi, Yechezkel; Panet, C.; Wasserman, Lina; Cyjon, Arnold; Novogrodsky, Abraham; Nordenberg, Jardena

doi:10.1038/bjc.1988.162

Cited by 30 publications

(10 citation statements)

References 15 publications

(15 reference statements)

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“…The measurement of [I4C]acetate incorporation into lipid confirms that these compound increase lipid synthesis on MCF-7 cells (data not shown). Lipid accumulation has been suggested to be a differentiated feature of breast cancer cell (Graham and Buick, 1988;Sidi et al, 1988). The results of the present study confirm and extend at the ultra-structural level previous reports (Abe and Kufe, 1984a,b;Valette et al, 1987) indicating that chemical compounds could induce in MCF-7 cells the morphological characteristics of a more differentiated cell.…”

Section: Tpa (8nm)supporting

confidence: 95%

Effects of differentiation‐inducing agents on maturation of human MCF‐7 breast cancer cells

Guilbaud

Gas

Dupont

et al. 1990

Journal Cellular Physiology

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The effects of the differentiation inducing agents (DIAS), sodium butyrate (NaBu), retinoic acid (RA), dimethylformamide (DMF), hexamethylene bisacetamide (HMBA), forskolin, and 12-O-tetradecanoylphorbol-13-acetate (TPA), on the growth, morphology, and estrogen receptor (ER) content and epithelial membrane antigen (EMA) expression on a serumless human breast cancer cell line (MCF-7) were compared. All these agents reversibly caused a concentration-dependent growth inhibition in monolayers and markedly reduced colony-forming efficiency in soft agar. A twofold increase in doubling time was obtained with RA (1 microM), but cell replication ceased with NaBu (1 mM), forskolin (50 microM), DMF (1%), HMBA (5 mM), and TPA (8 nM). Total growth arrest induced by these last compounds was preceded by an accumulation of cells in G0/G1 phase observed at 24 h by flow cytometry and accompanied by a change in cell morphology as seen by light and electronic microscopy. An increase in cell volume and the presence of lipid droplets was noted in treated cells that were spread out, as compared with controls. The acquisition of a more mature phenotype was confirmed by an increased expression of EMA monitored by flow cytometry. A specific reduction in the number of ER without any constant dissociation (Kd) modification was also observed after treatment with the 5 DIAs. No modification of morphological or biochemical characteristics, including EMA expression and ER binding, were observed for RA (1 microM)-treated cells. All these results suggest that induction of a more differentiated phenotype is associated with a block in G1 cell cycle phase, resulting in total growth arrest. Apparently, RA (1 microM)-treated cells did not fulfill these criteria, since only a slight accumulation in G1 and a slowed growth rate were evaluated.

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Section: Tpa (8nm)supporting

confidence: 95%

Effects of differentiation‐inducing agents on maturation of human MCF‐7 breast cancer cells

Guilbaud

Gas

Dupont

et al. 1990

Journal Cellular Physiology

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“…Recently there has been renewed interest in compounds which inhibit the activity of IMPDH, the enzyme that catalyzes the rate-limiting step in de novo purine biosynthesis by interconversion of IMP to XMP, as potential therapeutic agents in cancer (Lee ef al., 1985;Sidi et al, 1988;Grem et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Anti‐tumor activity of mycophenolate mofetil against human and mouse tumors in vivo

Tressler¹,

Garvin²,

Slate³

1994

Intl Journal of Cancer

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Cultured tumor cell lines, tumor xenografts grown in athymic nude mice, and a murine experimental metastasis model were used to assess the in vitro and in vivo anti-tumor activity of the potent IMP dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), and its morpholinoethyl ester pro-drug, mycophenolate mofetil (MM). The growth of all the cell lines tested was inhibited by MPA in vitro, with EC50 values ranging from less than 0.1 microM to 3.9 microM. Mice were monitored for s.c. tumor outgrowth in the case of human tumor xenograft models or survival time for the murine experimental metastasis model. Treatment with MM p.o. was started 24 hr after tumor challenge or after tumors became palpable. Treatment of athymic nude mice bearing A3.01 (T-lymphoblast), Molt-4 (T-cell leukemia), CaPan-2 (pancreatic adenocarcinoma), CaLu-3 (non-small-cell lung adenocarcinoma), LS174T and T84 (colon adenocarcinoma), and Daudi (B-cell lymphoma) human tumor xenografts with MM significantly inhibited s.c. tumor growth. Treatment of BALB/c mice with MM after i.v. injection of murine RAW117-H10 lymphoma cells in an experimental metastasis assay resulted in increased survival time for treated animals. No significant inhibitory effect on s.c. tumor outgrowth was seen with MM treatment of SK-Hep-1, a human hepatic endothelioma, or Hep-3B, a liver adenocarcinoma, at any of the doses tested.

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“…The observations that the activity of IMPDH is tightly linked with both cellular proliferation and transformation (1-3) have led to an interest in developing IMPDH inhibitors for clinical use. Inhibition of IMPDH activity is associated with depletion of intracellular guanine nucleotide pools and has been shown both to inhibit cellular proliferation (4,5) and to induce cell differentiation (6 -9). The specific reversibility by exogenous guanine of the biologic effects of IMPDH inhibitors on cell division and differentiation is a unique feature of such compounds that differentiates them from other inducers of cellular differentiation.…”

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confidence: 99%

Regulation of the Human Inosine Monophosphate Dehydrogenase Type I Gene

Spychała

Mitchell

1997

Journal of Biological Chemistry

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Catalysis of guanine nucleotide formation from IMP in the de novo purine synthetic pathway is carried out by two isoforms of the enzyme inosine monophosphate dehydrogenase (IMPDH) that are catalytically indistinguishable but are encoded by separate genes. In order to assess the potential for cell type-specific expression of IMPDH activity, we have characterized the IMPDH type I gene and identified three major RNA transcripts that are differentially expressed from three different promoters. A 4.0-kilobase pair (kb) mRNA containing 1.3 kb of 5-untranslated region is expressed in activated peripheral blood lymphocytes and to a far lesser extent in cultured tumor cell lines. The P1 promoter that regulates the transcription of this mRNA has a high degree of sequence identity to an Alu repetitive sequence. A transcript of 2.7 kb is found in a subset of the tumor cell lines examined, whereas a 2.5-kb mRNA species is universally expressed and is the prevalent mRNA in most cell lines and tissues. The relative strengths of the three promoter regions and the effects of variable extents of 5-flanking sequence on the P3 promoter differ in Jurkat T, as compared with Raji B lymphoid cell lines, demonstrating a complex cell type-specific transcriptional regulation of IMPDH type I gene expression.Inosine 5Ј-monophosphate dehydrogenase (IMPDH; 1 EC 1.1.1.205) is an essential, rate-limiting enzyme in the de novo guanine nucleotide synthetic pathway. It catalyzes the conversion of IMP to XMP at the purine metabolic branch point and provides sufficient guanine nucleotides for important cellular processes. The observations that the activity of IMPDH is tightly linked with both cellular proliferation and transformation (1-3) have led to an interest in developing IMPDH inhibitors for clinical use. Inhibition of IMPDH activity is associated with depletion of intracellular guanine nucleotide pools and has been shown both to inhibit cellular proliferation (4, 5) and to induce cell differentiation (6 -9). The specific reversibility by exogenous guanine of the biologic effects of IMPDH inhibitors on cell division and differentiation is a unique feature of such compounds that differentiates them from other inducers of cellular differentiation. IMPDH inhibitors have also been demonstrated to have considerable efficacy as immunosuppressive agents (10, 11) and prevent both B and T lymphocyte activation (12, 13).Human IMPDH activity is composed of the activities of two separate but very closely related IMPDH isoenzymes, termed type I and type II, that are encoded by separate genes located on chromosomes 7 and 3, respectively (14, 15). The corresponding cDNAs have been isolated (16, 17) and encode two distinct protein subunits of 56 kDa with 84% sequence identity. The two IMPDH proteins are tetrameric and are indistinguishable in their catalytic activities, substrate affinities, and K i values for known inhibitors (18 -20).The increased IMPDH activity observed in replicating or neoplastic cells is largely due to increased expression of the type I...

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Growth inhibition and induction of phenotypic alterations in MCF-7 breast cancer cells by an IMP dehydrogenase inhibitor

Abstract: Images Figure 2

Cited by 30 publications

References 15 publications

Effects of differentiation‐inducing agents on maturation of human MCF‐7 breast cancer cells

Effects of differentiation‐inducing agents on maturation of human MCF‐7 breast cancer cells

Anti‐tumor activity of mycophenolate mofetil against human and mouse tumors in vivo

Regulation of the Human Inosine Monophosphate Dehydrogenase Type I Gene

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