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Cancer Chemotherapy Reports Jul 1960
Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Dermatologic Agents; Humans; Plicamycin
PubMed: 13813365
DOI: No ID Found -
Lancet (London, England) May 1973
Topics: Aged; Female; Humans; Injections, Intravenous; Male; Middle Aged; Osteitis Deformans; Plicamycin
PubMed: 4123556
DOI: 10.1016/s0140-6736(73)91168-9 -
Chemico-biological Interactions Jan 2010Mithramycin is an inhibitor of the binding of the Sp-family transcription factor to the GC box. Many studies show that mithramycin may reduce the expression of many...
Mithramycin is an inhibitor of the binding of the Sp-family transcription factor to the GC box. Many studies show that mithramycin may reduce the expression of many oncogenes by inhibiting the mRNA and protein synthesis and it has been used as an antibiotic chemotherapy drug for a long time. Recently, Eps8 (EGFR pathway substrate 8) has been revealed to be a novel proto-oncogene related to cellular transformation, Rac activation and actin barbed-end-capping activity. Therefore, the aim of this study was to verify whether Eps8 might be regulated by mithramycin. Results showed that mithramycin could reduce the mRNA and protein levels of Eps8 in dose- and time-dependent manners in several cancer cell lines. Furthermore, cell growth and migration ability were also reduced significantly by mithramycin treatment. Since Src is a well-known Eps8 activity enhancer, a v-Src transfected IV5 cell line was subjected to mithramycin treatment and then analyzed to show that Src expression was unable to restore the mithramycin-induced decrease in Eps8 expression, cell growth, and migration ability. To further confirm the above mentioned results, the expression of Eps8 was eliminated by a transient transfection with siRNA and subsequent analysis showed that silencing of Eps8 might also lead to a reduced growth and migration ability of cancer cells. These findings suggested that Eps8 was involved in the regulation of growth and motility of cancer cells and mithramycin might exert its anticancer ability via a pathway involving the downregulation of Eps8.
Topics: Adaptor Proteins, Signal Transducing; Animals; Antibiotics, Antineoplastic; Carcinoma; Cell Line; Cell Movement; Cell Proliferation; Down-Regulation; Genes, src; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Mice; Plicamycin; Proto-Oncogene Mas; RNA, Small Interfering
PubMed: 19799886
DOI: 10.1016/j.cbi.2009.09.018 -
Journal of Neurotrauma Feb 2018After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption and progressive hemorrhage lead to secondary injury, subsequent apoptosis and/or necrosis of...
After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption and progressive hemorrhage lead to secondary injury, subsequent apoptosis and/or necrosis of neurons and glia, causing permanent neurological deficits. Growing evidence indicates that mithramycin A (MA), an anti-cancer drug, has neuroprotective effects in ischemic brain injury and Huntington's disease (HD). However, the precise mechanism underlying its protective effects is largely unknown. Here, we examined the effect of MA on BSCB breakdown and hemorrhage as well as subsequent inflammation after SCI. After moderate spinal cord contusion injury at T9, MA (150 μg/kg) was immediately injected intraperitoneally (i.p.) and further injected once a day for 5 days. Our data show that MA attenuated BSCB disruption and hemorrhage, and inhibited the infiltration of neutrophils and macrophages after SCI. Consistent with these findings, the expression of inflammatory mediators was significantly alleviated by MA. MA also inhibited the expression and activation of matrix metalloprotease-9 (MMP-9) after injury, which is known to disrupt BSCB and the degradation of tight junction (TJ) proteins. In addition, the expression of sulfonylurea receptor 1 (SUR1) and transient receptor potential melastatin 4 (TRPM4), which are known to mediate hemorrhage at an early stage after SCI, was significantly blocked by MA treatment. Finally, MA inhibited apoptotic cell death and improved functional recovery after injury. Thus, our results demonstrated that MA improves functional recovery by attenuating BSCB disruption and hemorrhage through the downregulation of SUR1/TRPM4 and MMP-9 after SCI.
Topics: Animals; Capillary Permeability; Hemorrhage; Male; Matrix Metalloproteinase 9; Neuroprotective Agents; Plicamycin; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries; Sulfonylurea Receptors; TRPM Cation Channels
PubMed: 29048243
DOI: 10.1089/neu.2017.5235 -
Molecular Genetics and Genomics : MGG Jan 2011The role of the ABCB8 gene in human cells is poorly understood, although it has been suggested to be involved in multidrug resistance in some types of cancers (e.g.,...
The role of the ABCB8 gene in human cells is poorly understood, although it has been suggested to be involved in multidrug resistance in some types of cancers (e.g., melanomas). In this study, the main mechanism of transcriptional regulation of the ABCB8 gene was characterized. EMSA and ChIP assays revealed that the transcription factor Sp1 binds to the ABCB8 core promoter region, and Sp1 consensus elements were crucial for promoter activity in a luciferase reporter gene assay. Mithramycin A, an inhibitor of Sp1 binding, downregulated the expression of ABCB8 (and other ABC genes) in a concentration-dependent manner and sensitized a melanoma cell line to doxorubicin treatment. These findings may have therapeutic applications in at least a subset of melanoma patients.
Topics: ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Cell Line, Tumor; Down-Regulation; Doxorubicin; Drug Resistance, Neoplasm; Electrophoretic Mobility Shift Assay; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Plicamycin; Promoter Regions, Genetic; Skin Neoplasms; Sp1 Transcription Factor
PubMed: 21046154
DOI: 10.1007/s00438-010-0586-8 -
The Journal of Neuroscience : the... May 2011Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic...
Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington's disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect. We identify several genes (Myc, c-Src, Hif1α, and p21(waf1/cip1)) involved in neoplastic transformation, whose altered expression correlates with protective doses of mithramycin or its analogs. Most interestingly, inhibition of one these genes, Myc, is neuroprotective, whereas forced expression of Myc induces Rattus norvegicus neuronal cell death. These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration.
Topics: Analysis of Variance; Animals; Animals, Genetically Modified; Antibiotics, Antineoplastic; Blotting, Western; Cell Survival; Cells, Cultured; Cerebral Cortex; Chromatin Immunoprecipitation; Drosophila; Neurons; Plicamycin; Rats; Rats, Sprague-Dawley; Sp1 Transcription Factor; Structure-Activity Relationship
PubMed: 21543616
DOI: 10.1523/JNEUROSCI.0710-11.2011 -
Translational Research : the Journal of... May 2015Chemotherapy resistance is a major clinical challenge for the management of locally advanced breast cancer. Accumulating evidence suggests a major role of cancer stem...
Chemotherapy resistance is a major clinical challenge for the management of locally advanced breast cancer. Accumulating evidence suggests a major role of cancer stem cells (CSCs) in chemoresistance evoking the requirement of drugs that selectively target CSCs in combination with chemotherapy. Here, we report that mithramycin A, a known specificity protein (Sp)1 inhibitor, sensitizes breast CSCs (bCSCs) by perturbing the expression of drug efflux transporters, ATP-binding cassette sub-family G, member 2 (ABCG2) and ATP-binding cassette sub-family C, member 1 (ABCC1), survival factors, B-cell lymphoma 2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and, stemness regulators, octamer-binding transcription factor 4 (Oct4) and Nanog, which are inherently upregulated in these cells compared with the rest of the tumor population. In-depth analysis revealed that aberrant overexpression of Sp1 in bCSCs transcriptionally upregulates (1) resistance-promoting genes to protect these cells from genotoxic therapy, and (2) stemness regulators to sustain self-renewal potential of these cells. However, mithramycin A causes transcriptional suppression of these chemoresistant and self-renewal genes by inhibiting Sp1 recruitment to their promoters. Under such antisurvival microenvironment, chemotherapeutic agent doxorubicin induces apoptosis in bCSCs via DNA damage-induced reactive oxygen species generation. Cumulatively, our findings raise the possibility that mithramycin A might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to eliminate CSCs. This will consequently lead to the improvement of therapeutic outcome for the treatment-resistant breast carcinomas.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; MCF-7 Cells; Middle Aged; Neoplastic Stem Cells; Plicamycin; Sp1 Transcription Factor; Spheroids, Cellular; Translational Research, Biomedical; Tumor Cells, Cultured; Tumor Microenvironment
PubMed: 25468484
DOI: 10.1016/j.trsl.2014.10.011 -
Scientific Reports Jan 2018As the most malignant breast cancer subtype, triple-negative breast cancer (TNBC) does not have effective targeted therapies clinically to date. As a selective Sp1...
As the most malignant breast cancer subtype, triple-negative breast cancer (TNBC) does not have effective targeted therapies clinically to date. As a selective Sp1 inhibitor, Mithramycin A (MIT) has been reported to have anti-tumor activities in multiple cancers. However, the efficacy and the mechanism of MIT in breast cancer, especially TNBC, have not been studied. In this study, we demonstrated that MIT suppressed breast cancer cell survival in a dosage-dependent manner. Interestingly, TNBC cells were more sensitive to MIT than non-TNBC cells. MIT inhibited TNBC cell proliferation and promoted apoptosis in vitro in time- and dosage-dependent manners. MIT suppressed TNBC cell survival, at least partially, by transcriptionally down-regulating KLF5, an oncogenic transcription factor specifically expressed in basal TNBC. Finally, MIT suppressed TNBC cell growth in a xenograft mouse model. Taken together, our findings suggested that MIT inhibits basal TNBC via the Sp1/KLF5 axis and that MIT may be used for TNBC treatment.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Kruppel-Like Transcription Factors; Plicamycin; Sp1 Transcription Factor; Transcription, Genetic; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays
PubMed: 29348684
DOI: 10.1038/s41598-018-19489-6 -
Molecular Cancer Therapeutics Nov 2006Mithramycin A is a DNA-binding antitumor agent, which has been clinically used in the therapies of several types of cancer and Paget's disease. In this study, we...
Mithramycin A is a DNA-binding antitumor agent, which has been clinically used in the therapies of several types of cancer and Paget's disease. In this study, we investigated the combined effect of mithramycin A and tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) on apoptosis of cancer cells. In Caki renal cancer cells, which are resistant to TRAIL, cotreatment with subtoxic doses of mithramycin A and TRAIL resulted in a marked increase in apoptosis. This combined treatment was also cytotoxic to Caki cells overexpressing Bcl-2 but not to normal mesengial cells. Moreover, apoptosis by the combined treatment with mithramycin A and TRAIL was dramatically induced in various cancer cell types, thus offering an attractive strategy for safely treating malignant tumors. Mithramycin A-stimulated TRAIL-induced apoptosis was blocked by pretreatment with the broad caspase inhibitor zVAD-fmk or Crm-A overexpression, showing its dependence on caspases. We found that mithramycin A selectively down-regulated XIAP protein levels in various cancer cells. Luciferase reporter assay and the chromatin immunoprecipitation assay using the XIAP promoter constructs show that mithramycin A down-regulates the transcription of XIAP gene through inhibition of Sp1 binding to its promoter. Although XIAP overexpression significantly attenuated apoptosis induced by mithramycin A plus TRAIL, suppression of XIAP expression by transfection with its small interfering RNA prominently enhanced TRAIL-induced apoptosis. 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.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Binding Sites; Breast Neoplasms; Carcinoma, Renal Cell; Caspases; Colonic Neoplasms; Down-Regulation; Female; HT29 Cells; Humans; Male; Plicamycin; Promoter Regions, Genetic; Sp1 Transcription Factor; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; X-Linked Inhibitor of Apoptosis Protein
PubMed: 17121920
DOI: 10.1158/1535-7163.MCT-06-0426 -
Annals of Internal Medicine Feb 1981
Topics: Adult; Aged; Humans; Leukemia; Lymphoma, Non-Hodgkin; Middle Aged; Neoplasms; Osteitis Deformans; Plicamycin
PubMed: 6451194
DOI: 10.7326/0003-4819-94-2-279_2