Genomes and Genes
Summary: A tricyclic pentaglycosidic antibiotic from Streptomyces strains that inhibits RNA and protein synthesis by adhering to DNA. It is used as a fluorescent dye and as an antineoplastic agent, especially in bone and testicular tumors. Plicamycin is also used to reduce hypercalcemia, especially that due to malignancies.
- Malek A, Núñez L, Magistri M, Brambilla L, Jovic S, Carbone G, et al. Modulation of the activity of Sp transcription factors by mithramycin analogues as a new strategy for treatment of metastatic prostate cancer. PLoS ONE. 2012;7:e35130 pubmed publisher..Taken together, these data indicate that MTM-SDK and MTM-SK possess significantly improved pharmacological and toxicological properties compared to MTM-A and represent promising drugs for treatment of advanced prostate cancer. ..
- Keniry M, Banville D, Simmonds P, Shafer R. Nuclear magnetic resonance comparison of the binding sites of mithramycin and chromomycin on the self-complementary oligonucleotide d(ACCCGGGT)2. Evidence that the saccharide chains have a role in sequence specificity. J Mol Biol. 1993;231:753-67 pubmed..Titration of mithramycin up to a drug-duplex ratio of 7:1 reveals further association of mithramycin with the complex but no new drug-oligonucleotide nuclear Overhauser enhancement contacts. ..
- Chatterjee S, Zaman K, Ryu H, Conforto A, Ratan R. Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons. Ann Neurol. 2001;49:345-54 pubmed..Mithramycin A (trade name Plicamycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers...
- Koutsodontis G, Kardassis D. Inhibition of p53-mediated transcriptional responses by mithramycin A. Oncogene. 2004;23:9190-200 pubmed
- Trefzer A, Blanco G, Remsing L, K nzel E, Rix U, Lipata F, et al. Rationally designed glycosylated premithramycins: hybrid aromatic polyketides using genes from three different biosynthetic pathways. J Am Chem Soc. 2002;124:6056-62 pubmed..The successful combination of two glycosyltransferases in the latter experiment proves that the design of saccharide side chains by combinatorial biosynthetic methods is possible...
- Grohar P, Woldemichael G, Griffin L, Mendoza A, Chen Q, Yeung C, et al. Identification of an inhibitor of the EWS-FLI1 oncogenic transcription factor by high-throughput screening. J Natl Cancer Inst. 2011;103:962-78 pubmed publisher..001). Mithramycin inhibits EWS-FLI1 activity and demonstrates ESFT antitumor activity both in vitro and in vivo. ..
- Duverger V, Murphy A, Sheehan D, England K, Cotter T, Hayes I, et al. The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF). Br J Cancer. 2004;90:2025-31 pubmed..These results indicate that mithramycin enhances TNF-induced cell death in an NF-kappaB-independent manner, and suggest that the Fas-associated death domain protein plays a crucial role in the TNF-sensitising effect of mithramycin. ..
- Jia Z, Zhang J, Wei D, Wang L, Yuan P, Le X, et al. Molecular basis of the synergistic antiangiogenic activity of bevacizumab and mithramycin A. Cancer Res. 2007;67:4878-85 pubmed..Therefore, this study is the first to show the significance and clinical implications of alteration of Sp1 signaling in antiangiogenic therapy for pancreatic cancer and other cancers. ..
- Jin H, Kanthasamy A, Anantharam V, Rana A, Kanthasamy A. Transcriptional regulation of pro-apoptotic protein kinase Cdelta: implications for oxidative stress-induced neuronal cell death. J Biol Chem. 2011;286:19840-59 pubmed publisher..Collectively, our findings may have implications for development of new translational strategies against oxidative damage. ..
- Chakraborty H, Devi P, Sarkar M, Dasgupta D. Multiple functions of generic drugs: future perspectives of aureolic acid group of anti-cancer antibiotics and non-steroidal anti-inflammatory drugs. Mini Rev Med Chem. 2008;8:331-49 pubmed..Here we have reviewed the molecular mechanism behind the multiple functions of these drugs that might lead to employ them for treatment of diseases in addition to those they are presently employed. ..
- Bianchi N, Zuccato C, Lampronti I, Borgatti M, Gambari R. Expression of miR-210 during erythroid differentiation and induction of gamma-globin gene expression. BMB Rep. 2009;42:493-9 pubmed..Altogether, the data suggest that miR-210 might be involved in increased expression of gamma-globin genes in differentiating erythroid cells. ..
- Cohen Sela E, Teitlboim S, Chorny M, Koroukhov N, Danenberg H, Gao J, et al. Single and double emulsion manufacturing techniques of an amphiphilic drug in PLGA nanoparticles: formulations of mithramycin and bioactivity. J Pharm Sci. 2009;98:1452-62 pubmed publisher..The ineffectiveness in the rat restenosis model is probably due to the short depletion period of circulating monocytes and lack of arterial targeting. ..
- Remsing L, Garcia Bernardo J, Gonzalez A, K nzel E, Rix U, Bra a A, et al. Ketopremithramycins and ketomithramycins, four new aureolic acid-type compounds obtained upon inactivation of two genes involved in the biosynthesis of the deoxysugar moieties of the antitumor drug mithramycin by Streptomyces argillaceus, reveal nove. J Am Chem Soc. 2002;124:1606-14 pubmed..The same is true for glycosyltransferases MtmGI and MtmGII, both of which partake in the formation and attachment of the A-B disaccharide in mithramycin...
- Ohgami T, Kato K, Kobayashi H, Sonoda K, Inoue T, Yamaguchi S, et al. Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers. Cancer Sci. 2010;101:1387-95 pubmed publisher..These observations provide a better understanding of the mechanisms of mithramycin activity, and suggest a potential role for combining mithramycin and nutlin-3 as a chemotherapeutic treatment for gynecologic cancers. ..
- Previdi S, Malek A, Albertini V, Riva C, Capella C, Broggini M, et al. Inhibition of Sp1-dependent transcription and antitumor activity of the new aureolic acid analogues mithramycin SDK and SK in human ovarian cancer xenografts. Gynecol Oncol. 2010;118:182-8 pubmed publisher..MTM-SDK and MTM-SK show relevant activity in vivo and represent interesting candidates for treatment of ovarian cancers. ..
- Tang T, Lin X, Yang H, Zhou L, Wang Z, Shan G, et al. Overexpression of antioxidant enzymes upregulates aryl hydrocarbon receptor expression via increased Sp1 DNA-binding activity. Free Radic Biol Med. 2010;49:487-92 pubmed publisher..These results suggest that increased Sp1 binding to the AhR promoter region is an underlying mechanism for upregulation of AhR expression in MAECs that overexpress Cu/Zn-SOD and/or catalase. ..
- Sastry M, Patel D. Solution structure of the mithramycin dimer-DNA complex. Biochemistry. 1993;32:6588-604 pubmed..abstract truncated at 400 words) ..
- Fern ndez E, Weissbach U, S nchez Reillo C, Bra a A, M ndez C, Rohr J, et al. Identification of two genes from Streptomyces argillaceus encoding glycosyltransferases involved in transfer of a disaccharide during biosynthesis of the antitumor drug mithramycin. J Bacteriol. 1998;180:4929-37 pubmed
- Prado L, Fern ndez E, Weissbach U, Blanco G, Quir s L, Bra a A, et al. Oxidative cleavage of premithramycin B is one of the last steps in the biosynthesis of the antitumor drug mithramycin. Chem Biol. 1999;6:19-30 pubmed..The following decarboxylation and ketoreduction steps lead to mithramycin. Opening of the fourth ring represents one of the last steps in mithramycin biosynthesis...
- Lozano M, Remsing L, Quir s L, Bra a A, Fern ndez E, S nchez C, et al. Characterization of two polyketide methyltransferases involved in the biosynthesis of the antitumor drug mithramycin by Streptomyces argillaceus. J Biol Chem. 2000;275:3065-74 pubmed..A pathway is proposed for the last steps in the biosynthesis of mithramycin involving these methylation events...
- Ahn S, Cho C, Park K, Lee H, Lee S, Park S, et al. Tumor necrosis factor-alpha induces fractalkine expression preferentially in arterial endothelial cells and mithramycin A suppresses TNF-alpha-induced fractalkine expression. Am J Pathol. 2004;164:1663-72 pubmed..NF-kappaB and Sp1 inhibitors such as mithramycin A may provide a pharmacological approach to suppressing these processes. ..
- Yuan P, Wang L, Wei D, Zhang J, Jia Z, Li Q, et al. Therapeutic inhibition of Sp1 expression in growing tumors by mithramycin a correlates directly with potent antiangiogenic effects on human pancreatic cancer. Cancer. 2007;110:2682-90 pubmed
- Lampronti I, Bianchi N, Borgatti M, Fibach E, Prus E, Gambari R. Accumulation of gamma-globin mRNA in human erythroid cells treated with angelicin. Eur J Haematol. 2003;71:189-95 pubmed
- Menéndez N, Brana A, Salas J, Mendez C. Involvement of a chromomycin ABC transporter system in secretion of a deacetylated precursor during chromomycin biosynthesis. Microbiology. 2007;153:3061-70 pubmed..A model is proposed for the biosynthesis of, and self-resistance to, chromomycin A(3) in S. griseus subsp. griseus. ..
- Seznec J, Silkenstedt B, Naumann U. Therapeutic effects of the Sp1 inhibitor mithramycin A in glioblastoma. J Neurooncol. 2011;101:365-77 pubmed publisher..Therefore, MitA might be a potential agent to reduce glioma cell migration. ..
- Barceló F, Ortiz Lombardia M, Martorell M, Oliver M, Mendez C, Salas J, et al. DNA binding characteristics of mithramycin and chromomycin analogues obtained by combinatorial biosynthesis. Biochemistry. 2010;49:10543-52 pubmed publisher..Among the analogues, mithramycin SDK and chromomycin SDK possessed the higher DNA binding affinities. ..
- Sastry M, Fiala R, Patel D. Solution structure of mithramycin dimers bound to partially overlapping sites on DNA. J Mol Biol. 1995;251:674-89 pubmed
- Lombo F, Menéndez N, Salas J, Mendez C. The aureolic acid family of antitumor compounds: structure, mode of action, biosynthesis, and novel derivatives. Appl Microbiol Biotechnol. 2006;73:1-14 pubmed..Heterologous expression of biosynthetic genes from other aromatic polyketide pathways in the mithramycin producer (or some mutants) led to the isolation of novel hybrid compounds. ..
- Christensen M, Zhou W, Qing H, Lehman A, Philipsen S, Song W. Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1. Mol Cell Biol. 2004;24:865-74 pubmed
- Gao Y, Jia Z, Kong X, Li Q, Chang D, Wei D, et al. Combining betulinic acid and mithramycin a effectively suppresses pancreatic cancer by inhibiting proliferation, invasion, and angiogenesis. Cancer Res. 2011;71:5182-93 pubmed publisher..Overall, our findings argue that Sp1 is an important target of BA and MIT and that their combination can produce an enhanced therapeutic response in human pancreatic cancer. ..
- Barceló F, Scotta C, Ortiz Lombardia M, Mendez C, Salas J, Portugal J. Entropically-driven binding of mithramycin in the minor groove of C/G-rich DNA sequences. Nucleic Acids Res. 2007;35:2215-26 pubmed..Direct molecular recognition between MTA or MSK and DNA through hydrogen bonding and van der Waals contacts may also contribute significantly to complex formation. ..
- Post S, Quintas Cardama A, Pant V, Iwakuma T, Hamir A, Jackson J, et al. A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell. 2010;18:220-30 pubmed publisher..These data provide causal evidence for increased cancer risk in carriers of the Mdm2(SNP309G) allele. ..
- Trisciuoglio D, Iervolino A, Candiloro A, Fibbi G, Fanciulli M, Zangemeister Wittke U, et al. bcl-2 induction of urokinase plasminogen activator receptor expression in human cancer cells through Sp1 activation: involvement of ERK1/ERK2 activity. J Biol Chem. 2004;279:6737-45 pubmed..In conclusion, our results strongly indicate that up-regulation of uPAR expression by Bcl-2 in hypoxia is modulated by Sp1 DNA binding activity through the ERK signaling pathway. ..
- Mir M, Majee S, Das S, Dasgupta D. Association of chromatin with anticancer antibiotics, mithramycin and chromomycin A3. Bioorg Med Chem. 2003;11:2791-801 pubmed..Significance of these results to understand the molecular basis of the transcription inhibition potential of the antibiotics in eukaryotes is discussed. ..
- Bianchi N, Osti F, Rutigliano C, Corradini F, Borsetti E, Tomassetti M, et al. The DNA-binding drugs mithramycin and chromomycin are powerful inducers of erythroid differentiation of human K562 cells. Br J Haematol. 1999;104:258-65 pubmed..Erythroid differentiation was associated with an increase in the accumulation of (a) Hb Gower 1 and Hb Portland and (b) gamma-globin mRNA. ..
- Ferrante R, Ryu H, Kubilus J, D MELLO S, Sugars K, Lee J, et al. Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington's disease. J Neurosci. 2004;24:10335-42 pubmed..Because it is Food and Drug Administration-approved, mithramycin is a promising drug for the treatment of HD. ..
- Baig I, Perez M, Brana A, Gomathinayagam R, DAMODARAN C, Salas J, et al. Mithramycin analogues generated by combinatorial biosynthesis show improved bioactivity. J Nat Prod. 2008;71:199-207 pubmed publisher..6 +/- 2% and 12.6 +/- 2.5% induction of apoptosis, respectively), which is not inhibited by the parent drug MTM itself (2.6 +/- 1.5% induction of apoptosis), but for which chemotherapeutic agents are urgently needed. ..
- Fibach E, Bianchi N, Borgatti M, Prus E, Gambari R. Mithramycin induces fetal hemoglobin production in normal and thalassemic human erythroid precursor cells. Blood. 2003;102:1276-81 pubmed..The results of this report suggest that mithramycin and its analogs warrant further evaluation as potential therapeutic drugs. ..
- Blanco G, Fern ndez E, Fern ndez M, Bra a A, Weissbach U, K nzel E, et al. Characterization of two glycosyltransferases involved in early glycosylation steps during biosynthesis of the antitumor polyketide mithramycin by Streptomyces argillaceus. Mol Gen Genet. 2000;262:991-1000 pubmed..These experiments demonstrate that the glycosyltransferases MtmGIV and MtmGIII catalyze the first two glycosylation steps in mithramycin biosynthesis. A model is proposed for the glycosylation steps in mithramycin biosynthesis...
- Wohlert S, K nzel E, Machinek R, M ndez C, Salas J, Rohr J. The structure of mithramycin reinvestigated. J Nat Prod. 1999;62:119-21 pubmed publisher..The structure elucidation was carried out with mithramycin decaacetate (4) using 2D NMR methods, including TOCSY, HMBC, and HSQC experiments. The work resulted in structure 3being confirmed for mithramycin...
- Lee T, Jung E, Lee J, Kim S, Park J, Choi K, et al. Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites. Mol Cancer Ther. 2006;5:2737-46 pubmed..We present here for the first time that mithramycin A-induced suppression of XIAP transcription plays a critical role in the recovery of TRAIL sensitivity in various cancer cells. ..
- Wang L, Guan X, Zhang J, Jia Z, Wei D, Li Q, et al. Targeted inhibition of Sp1-mediated transcription for antiangiogenic therapy of metastatic human gastric cancer in orthotopic nude mouse models. Int J Oncol. 2008;33:161-7 pubmed
- Gibson M, Nur E Alam M, Lipata F, Oliveira M, Rohr J. Characterization of kinetics and products of the Baeyer-Villiger oxygenase MtmOIV, the key enzyme of the biosynthetic pathway toward the natural product anticancer drug mithramycin from Streptomyces argillaceus. J Am Chem Soc. 2005;127:17594-5 pubmed..This is the first example in which a bacterial enzyme was unequivocally proven to act as Baeyer-Villigerase with its natural substrate, that is, in its natural context. ..
- Remsing L, Gonz lez A, Nur E Alam M, Fern ndez Lozano M, Bra a A, Rix U, et al. 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. J Am Chem Soc. 2003;125:5745-53 pubmed publisher..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...
- Tagashira M, Kitagawa T, Isonishi S, Okamoto A, Ochiai K, Ohtake Y. Mithramycin represses MDR1 gene expression in vitro, modulating multidrug resistance. Biol Pharm Bull. 2000;23:926-9 pubmed..Furthermore, MTM sensitized the cells against adriamycin. These results suggest that MTM would be a useful modulator of MDR induced by Pgp. ..
- Bataller M, Mendez C, Salas J, Portugal J. Mithramycin SK modulates polyploidy and cell death in colon carcinoma cells. Mol Cancer Ther. 2008;7:2988-97 pubmed publisher..The p53(-/-) cells died mainly from G2-M through early p53-independent apoptosis, which appeared to be mediated by caspase-2, although secondary necrosis was also observed. ..
- Lee E, Park H, Hwang J, Park D, Chang K, Kim C. Mithramycin inhibits etoposide resistance in glucose-deprived HT-29 human colon carcinoma cells. J Microbiol Biotechnol. 2007;17:1856-61 pubmed..The etoposide-chemosensitive action of mithramycin was just dependent on strict low glucose conditions, and resulted in the selective cell death of etoposide-resistant HT-29 human colon cancer cells. ..
- Hata Y, Kominato Y, Takizawa H. Identification and characterization of a novel antisense RNA transcribed from the opposite strand of the human blood group ABO gene. Transfusion. 2007;47:842-51 pubmed..These results suggest that ABOAS transcribed from the opposite strand of the ABO gene might be involved in the regulation of ABO gene expression. ..
- Gambari R, Feriotto G, Rutigliano C, Bianchi N, Mischiati C. Biospecific interaction analysis (BIA) of low-molecular weight DNA-binding drugs. J Pharmacol Exp Ther. 2000;294:370-7 pubmed..Therefore, this method could be used to identify new drugs exhibiting differential binding activities to selected regions of viral and eukaryotic gene promoters. ..
- Blanco G, Fu H, Mendez C, Khosla C, Salas J. Deciphering the biosynthetic origin of the aglycone of the aureolic acid group of anti-tumor agents. Chem Biol. 1996;3:193-6 pubmed..The final steps in the aglycone biosynthetic pathway presumably involve decarboxylation and oxidative cleavage between C-18 and C-19, followed by additional oxidation, reduction, and methylation reactions. ..
- Hou M, Lu W, Huang C, Fan R, Yuann J. Effects of polyamines on the DNA-reactive properties of dimeric mithramycin complexed with cobalt(II): implications for anticancer therapy. Biochemistry. 2009;48:4691-8 pubmed publisher..Our study suggests a novel method for enhancing the anticancer activity of DNA-binding metalloantibiotics through polyamine depletion...
- Cai F, Chen B, Zhou W, Zis O, Liu S, Holt R, et al. SP1 regulates a human SNAP-25 gene expression. J Neurochem. 2008;105:512-23 pubmed publisher..These results suggest that SP1 plays an important role in regulation of the human SNAP-25 gene expression. ..
- Thanseem I, Anitha A, Nakamura K, Suda S, Iwata K, Matsuzaki H, et al. Elevated transcription factor specificity protein 1 in autistic brains alters the expression of autism candidate genes. Biol Psychiatry. 2012;71:410-8 pubmed publisher..The diverse downstream pathways mediated by the Sp1-regulated genes, along with the environmental and intracellular signal-related regulation of Sp1, could explain the complex phenotypes associated with autism. ..
- Rao M, Atay S, Shukla V, Hong Y, Upham T, Ripley R, et al. Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells. Clin Cancer Res. 2016;22:1197-210 pubmed publisher..These findings provide preclinical rationale for phase II evaluation of mithramycin in patients with mesothelioma. ..
- Inada S, Ikeda Y, Suehiro T, Takata H, Osaki F, Arii K, et al. Glucose enhances protein tyrosine phosphatase 1B gene transcription in hepatocytes. Mol Cell Endocrinol. 2007;271:64-70 pubmed..Our data suggested that glucose enhanced PTP1B transcription through Sp1 activation by PKC. Increased hepatic PTP1B expression may partly explain glucose toxicity in diabetes. ..
- Ohsaka Y, Nishino H. Cooling-increased phospho-?-arrestin-1 and ?-arrestin-1 expression levels in 3T3-L1 adipocytes. Cryobiology. 2012;65:12-20 pubmed publisher..Our findings provide helpful information for clarifying the cold-responsive machinery for ?-arrestin-1 and elucidating low-temperature responses. ..