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Archives of Biochemistry and Biophysics Sep 2008Transcription factor E1AF is widely known to play critical roles in tumor metastasis via directly binding to the promoters of genes involved in tumor migration and...
Transcription factor E1AF is widely known to play critical roles in tumor metastasis via directly binding to the promoters of genes involved in tumor migration and invasion. Here, we reported for the first time the pro-apoptotic role of E1AF in tumor cells. The expression of E1AF at protein level was obviously increased during Huh-7 and Hep3B cells apoptosis induced by the anticancer agent mithramycin A. E1AF overexpression markedly enhanced mithramycin A-induced Huh-7 cell apoptosis and the expression of pro-apoptotic protein Bax depending on its DNA-binding domain. And, reduction of E1AF inhibited mithramycin A-induced Huh-7 cell apoptosis. Furthermore, reducing the expression of Bax significantly inhibited E1AF-increased Huh-7 cell apoptosis induced by mithramycin A. Taken together, E1AF increases mithramycin A-induced Huh-7 cells apoptosis and Bax expression depending on its DNA-binding domain, indicating that E1AF might contribute to the therapeutic efficiency of mithramycin A for hepatoma.
Topics: Adenovirus E1A Proteins; Apoptosis; Base Sequence; Blotting, Western; Cell Line; Cisplatin; DNA; DNA Primers; Flow Cytometry; Fluorouracil; Humans; Plicamycin; Protein Structure, Tertiary; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ets; Reverse Transcriptase Polymerase Chain Reaction; bcl-2-Associated X Protein
PubMed: 18510939
DOI: 10.1016/j.abb.2008.05.001 -
The Journal of Urology Mar 1972
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Hemorrhagic Disorders; Humans; L-Lactate Dehydrogenase; Male; Neoplasm Metastasis; Neoplasms, Experimental; Plicamycin; Remission, Spontaneous; Teratoma; Testicular Neoplasms; Time Factors
PubMed: 4258726
DOI: 10.1016/s0022-5347(17)61046-2 -
European Journal of Intensive Care... Dec 1975Twenty-nine patients with acute hypercalcemia secondary to carcinoma, myeloma and parathyroid adenoma have been treated with large doses of furosemide, mithramycin, or...
Twenty-nine patients with acute hypercalcemia secondary to carcinoma, myeloma and parathyroid adenoma have been treated with large doses of furosemide, mithramycin, or salmon calcitonin perfusion. With furosemide administration the treatment was successful in 6 of 10 patients. Furosemide was injected intravenously at the rate of 125 mg every 3 hours. With mithramycin perfusion only 2 of 8 patients have a return of the serum calcium levels to normal. With salmon thyrocalcitonin 3 of 10 patients obtained a good result. It can be interesting to suggest the association of furosemide and salmon calcitonin infusion to treat hypercalcemia of myeloma.
Topics: Adenoma; Adult; Aged; Calcitonin; Carcinoma; Esophageal Neoplasms; Furosemide; Humans; Hypercalcemia; Middle Aged; Multiple Myeloma; Parathyroid Neoplasms; Plicamycin
PubMed: 130239
DOI: 10.1007/BF00624436 -
Neurochemical Research Aug 2016Increasing evidence has shown that specificity protein 1 (Sp1) is abnormally increased in the brains of subjects with Alzheimer's disease (AD) and transgenic AD models....
Increasing evidence has shown that specificity protein 1 (Sp1) is abnormally increased in the brains of subjects with Alzheimer's disease (AD) and transgenic AD models. However, whether the Sp1 activation plays a critical role in the AD pathogenesis and selective inhibition of Sp1 activation may have a disease-modifying effect on the AD-like phenotypes remain elusive. In this study, we reported that Sp1 mRNA and protein expression were markedly increased in the brain of APPswe/PS1dE9 transgenic mice, whereas chronic administration of mithramycin A (MTM), a selective Sp1 inhibitor, potently inhibited Sp1 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, we found that MTM treatment resulted in a significant improvement of learning and memory deficits, a dramatic reduction in cerebral Aβ levels and plaque burden, a profound reduction in tau hyperphosphorylation, and a marked increase in synaptic marker in the APPswe/PS1dE9 mice. In addition, MTM treatment was powerfully effective in inhibiting amyloid precursor protein (APP) processing via suppressing APP, beta-site APP cleaving enzyme 1 (BACE1), and presenilin-1 (PS1) mRNA and protein expression to preclude Aβ production in the APPswe/PS1dE9 mice. Furthermore, MTM treatment strongly inhibited phosphorylated CDK5 and GSK3β signal pathways to reduce tau hyperphosphorylation in the APPswe/PS1dE9 mice. Collectively, our findings provide evidence that Sp1 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. The present study highlights that selective Sp1 inhibitors may be considered as disease-modifying therapeutic agents for AD.
Topics: Alzheimer Disease; Animals; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Hippocampus; Male; Mice; Mice, Transgenic; Plicamycin; Sp1 Transcription Factor
PubMed: 27072684
DOI: 10.1007/s11064-016-1903-3 -
Biological & Pharmaceutical Bulletin Aug 2000The effect of an aureolic acid, mithramycin (MTM) on multidrug resistance (MDR) was investigated. At a concentration of 0.02--0.1 mg/ml (about 20--90 microM), MTM...
The effect of an aureolic acid, mithramycin (MTM) on multidrug resistance (MDR) was investigated. At a concentration of 0.02--0.1 mg/ml (about 20--90 microM), MTM repressed MDR1 gene transcription of SBC-3/ADM, a MDR-phenotype subline derived from human small cell lung tumor. Under the same conditions, another aureolic acid, chromomycin A3, showed potent cytotoxicity. FACS analysis revealed that 5 microm MTM depleted the P-glycoprotein (Pgp) and lowered the efflux activity of SBC-3/ADM cells. Furthermore, MTM sensitized the cells against adriamycin. These results suggest that MTM would be a useful modulator of MDR induced by Pgp.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adult; Antineoplastic Agents; Base Sequence; DNA Primers; Doxorubicin; Drug Resistance, Multiple; Gene Expression Regulation; Humans; Male; Plicamycin; Transcription, Genetic; Tumor Cells, Cultured
PubMed: 10963297
DOI: 10.1248/bpb.23.926 -
Circulation Nov 1994Smooth muscle proliferation and extracellular matrix formation in the subintimal region of blood vessels that have been subjected to intimal injury are responsible for...
BACKGROUND
Smooth muscle proliferation and extracellular matrix formation in the subintimal region of blood vessels that have been subjected to intimal injury are responsible for restenosis following balloon angioplasty of the coronary arteries and for accelerated atherosclerosis in a variety of other pathophysiological states. The immediate early-response gene c-myc is overexpressed in proliferating vascular smooth muscle cells in vitro, and c-myc antisense oligomers have been shown to reduce c-myc expression and to inhibit proliferation of vascular smooth muscle cells in culture. Mithramycin is a commercially available G-C-specific DNA binding drug that selectively inhibits transcription of genes, such as c-myc, that have G-C-rich promoter sequences. This study tested the hypothesis that mithramycin inhibits transcription of the c-myc proto-oncogene and prevents myointimal proliferation after balloon injury of the rat carotid artery in vivo.
METHODS AND RESULTS
Ten-week-old male Sprague-Dawley rats received mithramycin (150 micrograms/kg IP) or distilled H2O 1 hour before and 1 hour after balloon injury of the right common carotid artery. After 2 weeks, the rats were killed by overdose of pentobarbital, and the injured right and uninjured control left arteries were pressure-fixed and subjected to morphological analysis for evaluation of the degree of myointimal thickening. Separate groups of rats were killed at 2 and 6 hours after vascular injury, and total RNA from injured and control vessels of mithramycin- and vehicle-treated rats was subjected to Northern analysis for assessment of steady-state c-myc mRNA levels. The areas of neointima and the ratios of neointimal to medial area were significantly less in mithramycin-treated than in control rats (0.6 +/- 0.1 versus 1.2 +/- 0.1 mm2, P < .01 and 95 +/- 16% versus 190 +/- 14%, P < .01). Lumen size was significantly greater in mithramycin-treated than in control rats (1.5 +/- 0.1 versus 0.8 +/- 0.1 mm2, P < .01). Steady-state c-myc mRNA levels were increased 10-fold and 2-fold (compared with undamaged carotid arteries) at 2 and 6 hours after balloon injury, respectively; mithramycin treatment reduced c-myc mRNA levels at 2 and 6 hours by 66% and 53%, respectively.
CONCLUSIONS
These results support the hypothesis that systemic administration of mithramycin immediately (1 hour before and after intervention effectively inhibits transcription of the c-myc proto-oncogene and prevents myointimal proliferation after balloon injury of the rat carotid artery in vivo. Because mithramycin has been shown to be well tolerated by humans and to effectively inhibit transcription of c-myc in proliferating human cells, this agent may be useful in the prevention of coronary restenosis.
Topics: Angioplasty, Balloon; Animals; Base Sequence; Carotid Arteries; Cell Division; Genes, myc; Male; Molecular Sequence Data; Muscle, Smooth, Vascular; Plicamycin; Proto-Oncogene Mas; RNA, Messenger; Rats; Rats, Sprague-Dawley
PubMed: 7955204
DOI: 10.1161/01.cir.90.5.2468 -
Biomedical Chromatography : BMC Aug 2019Mithramycin (MTM) has potent anticancer activity, but severe toxicities restrict its clinical use. Semi-synthetic approaches have yielded novel MTM analogs with...
Mithramycin (MTM) has potent anticancer activity, but severe toxicities restrict its clinical use. Semi-synthetic approaches have yielded novel MTM analogs with potentially lower toxicity and similar efficacy. In an effort to transition these analogs into in vivo models, a bioanalytical method was developed for their quantification in mouse plasma. Here we present the validation of the method for the quantitation of mithramycin SA-tryptophan (MTMSA-Trp) as well as the applicability of the methodology for assaying additional analogs, including MTM, mithramycin SK (MTMSK) and mithramycin SA-phenylalanine (MTMSA-Phe) with run times of 6 min. Assay linearity ranged from 5 to 100 ng/mL. Accuracies of calibration standards and quality control samples were within 15% of nominal with precision variability of <20%. MTMSA-Trp was stable for 30 days at -80°C and for at least three freeze-thaw cycles. Methanol (-80°C) extraction afforded 92% of MTMSA-Trp from plasma. Calibration curves for MTM and analogs were also linear from ≤5 to 100 ng/mL. This versatile method was used to quantitate MTM analogs in plasma samples collected during preclinical pharmacokinetic studies.
Topics: Animals; Antibiotics, Antineoplastic; Chromatography, High Pressure Liquid; Drug Stability; Female; Limit of Detection; Linear Models; Mass Spectrometry; Mice; Plicamycin; Reproducibility of Results
PubMed: 30927450
DOI: 10.1002/bmc.4544 -
International Journal of Nanomedicine 2012This report shows that the DNA-binding drug, mithramycin, can be efficiently encapsulated in polymeric micelles (PM-MTH), based on Pluronic(®) block copolymers, by a...
This report shows that the DNA-binding drug, mithramycin, can be efficiently encapsulated in polymeric micelles (PM-MTH), based on Pluronic(®) block copolymers, by a new microfluidic approach. The effect of different production parameters has been investigated for their effect on PM-MTH characteristics. The compared analysis of PM-MTH produced by microfluidic and conventional bulk mixing procedures revealed that microfluidics provides a useful platform for the production of PM-MTH with improved controllability, reproducibility, smaller size, and polydispersity. Finally, an investigation of the effects of PM-MTH, produced by microfluidic and conventional bulk mixing procedures, on the erythroid differentiation of both human erythroleukemia and human erythroid precursor cells is reported. It is demonstrated that PM-MTH exhibited a slightly lower toxicity and more pronounced differentiative activity when compared to the free drug. In addition, PM-MTH were able to upregulate preferentially γ-globin messenger ribonucleic acid production and to increase fetal hemoglobin (HbF) accumulation, the percentage of HbF-containing cells, and their HbF content without stimulating α-globin gene expression, which is responsible for the clinical symptoms of β-thalassemia. These results represent an important first step toward a potential clinical application, since an increase in HbF could alleviate the symptoms underlying β-thalassemia and sickle cell anemia. In conclusion, this report suggests that PM-MTH produced by microfluidic approach warrants further evaluation as a potential therapeutic protocol for β-thalassemia.
Topics: Analysis of Variance; Cell Differentiation; Cells, Cultured; Chemistry, Pharmaceutical; Erythrocytes; Erythroid Precursor Cells; Humans; K562 Cells; Lab-On-A-Chip Devices; Micelles; Microfluidics; Plicamycin; Polymers; Reproducibility of Results; beta-Thalassemia
PubMed: 22287841
DOI: 10.2147/IJN.S25657 -
Journal of the American Chemical Society May 2003To gain initial structure-activity relationships regarding the highly functionalized pentyl side chain attached at C-3 of mithramycin (MTM), we focused on a...
Mithramycin SK, a novel antitumor drug with improved therapeutic index, mithramycin SA, and demycarosyl-mithramycin SK: three new products generated in the mithramycin producer Streptomyces argillaceus through combinatorial biosynthesis.
To gain initial structure-activity relationships regarding the highly functionalized pentyl side chain attached at C-3 of mithramycin (MTM), we focused on a post-polyketide synthase (post-PKS) tailoring step of the MTM biosynthesis by Streptomyces argillaceus ATCC 12956, which was proposed to be catalyzed by ketoreductase (KR) MtmW. In this last step of the MTM biosynthesis, a keto group of the pentyl side chain is reduced to a secondary alcohol, and we anticipated the generation of an MTM derivative with an additional keto group in the 3-side chain. Insertional inactivation of mtmW, a gene located ca. 8 kb downstream of the mithramycin-PKS genes, yielded an S. argillaceus mutant, which accumulated three new mithramycin analogues, namely mithramycin SA, demycarosyl-mithramycin SK, and mithramycin SK (MTM-SK). The structures of these three compounds confirmed indirectly the proposed role of MtmW in MTM biosynthesis. However, the new mithramycin derivatives bear unexpectedly shorter 3-side chains (ethyl or butyl) than MTM, presumably caused by nonenzymatic rearrangement or cleavage reactions of the initially formed pentyl side chain with a reactive beta-dicarbonyl functional group. The major product, MTM-SK, was tested in vitro against a variety of human cancer cell lines, as well as in an in vitro toxicity assay, and showed an improved therapeutic index, in comparison to the parent drug, MTM.
Topics: Antibiotics, Antineoplastic; Carbohydrate Sequence; Combinatorial Chemistry Techniques; Drug Screening Assays, Antitumor; Gene Silencing; Humans; Molecular Sequence Data; Mutagenesis, Insertional; Nuclear Magnetic Resonance, Biomolecular; Oxidoreductases; Plicamycin; Streptomyces; Trisaccharides; Tumor Cells, Cultured
PubMed: 12733914
DOI: 10.1021/ja034162h -
Hematological Oncology 1991After reports of the successful use of mithramycin and hydroxyurea in the myeloid blast phase of chronic granulocytic leukemia, we treated nine patients according to the... (Clinical Trial)
Clinical Trial Review
After reports of the successful use of mithramycin and hydroxyurea in the myeloid blast phase of chronic granulocytic leukemia, we treated nine patients according to the protocol devised by Koller and Miller (1986). There were no complete responses, but one patient had a partial response with a transient return to the chronic phase. Of the remaining eight patients, two experienced lessening of bone pains, and one a reduction in spleen size, but without hematological improvement. The regimen was associated with significant toxicity, and no overall survival advantage. We present a review of published data regarding the use of mithramycin in chronic granulocytic leukemia which supports the results in our series. The combination of mithramycin and hydroxyurea is largely ineffective in the blast phase of chronic granulocytic leukemia, but may be of value in the accelerated phase.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Middle Aged; Plicamycin
PubMed: 1828453
DOI: 10.1002/hon.2900090103