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Chemical Biology & Drug Design May 2013Mithramycin (MTM) is a potent anti-cancer agent that has recently garnered renewed attention. This manuscript describes the design and development of mithramycin...
Mithramycin (MTM) is a potent anti-cancer agent that has recently garnered renewed attention. This manuscript describes the design and development of mithramycin derivatives through a combinational approach of biosynthetic analogue generation followed by synthetic manipulation for further derivatization. Mithramycin SA is a previously discovered analogue produced by the M7W1 mutant strain alongside the improved mithramycin analogues mithramycin SK and mithramycin SDK. Mithramycin SA shows decreased anti-cancer activity compared to mithramycin and has a shorter, two carbon aglycon side chain that is terminated in a carboxylic acid. The aglycon side chain is responsible for an interaction with the DNA-phosphate backbone as mithramycin interacts with its target DNA. It was therefore decided to further functionalize this side chain through reactions with the terminal carboxylic acid in an effort to enhance the interaction with the DNA phosphate backbone and improve the anti-cancer activity. This side chain was modified with a variety of molecules increasing the anti-cancer activity to a comparable level to mithramycin SK. This work shows the ability to transform the previously useless mithramycin SA into a valuable molecule and opens the door to further functionalization and semi-synthetic modification for the development of molecules with increased specificity and/or drug formulation.
Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; DNA, Neoplasm; Drug Screening Assays, Antitumor; Humans; Neoplasms; Plicamycin
PubMed: 23331575
DOI: 10.1111/cbdd.12107 -
European Spine Journal : Official... Oct 2001A review of the literature was conducted to study the pathomechanics by which Paget's Disease of bone (PD) alters the spinal structures that result in distinct spinal... (Review)
Review
A review of the literature was conducted to study the pathomechanics by which Paget's Disease of bone (PD) alters the spinal structures that result in distinct spinal pathologic entities such as pagetic spinal arthritis, spinal stenosis, and other pathologies, and to assess the best treatment options and available drugs. The spine is the second most commonly affected site with PD. About one-third of patients with spinal involvement exhibit symptoms of clinical stenosis. In only 12-24% of patients with PD of the spine is back pain attributed solely to PD, while in the majority of patients back pain is either arthritic in nature or a combination of a pagetic process and coexisting arthritis. Neural element dysfunction may be attributed to compressive myelopathy by pagetic bone overgrowth, pagetic intraspinal soft tissue overgrowth, ossification of epidural fat, platybasia, spontaneous bleeding, sarcomatous degeneration and vertebral fracture or subluxation. Neural dysfunction can also result from spinal ischemia, when blood is diverted by the so-called "arterial steal syndrome". Because the effectiveness of pharmacologic treatment for pagetic spinal stenosis has been clearly demonstrated, surgical decompression should only be instituted after failure of antipagetic medical treatment. Surgery is indicated as a primary treatment when neural compression is secondary to pathologic fractures, dislocations, spontaneous epidural hematoma, syringomyelia, platybasia, or sarcomatous transformation. Since, in the majority of cases with pagetic spinal involvement, there are also coexisting osteoarthritic changes, antipagetic medical treatment alone may be disappointing. Therefore, one must be careful before attributing low back pain to PD alone. Five classes of drugs are available for the treatment of PD: bisphosphonates, calcitonins, mithramycin (plicamycin), gallium nitrate, and ipriflavone. Bisphosphonates are the most popular, and several forms have been investigated, but only the following forms have been approved for clinical use: disodium etidronate, clodronate, aledronate, risedronate, neridronate, pamidronate, tiludronate, ibadronate, aminohydroxylbutylidene bisphosphonate, olpadronate, and zoledronate. Several of these forms are still under investigation.
Topics: Humans; Osteitis Deformans; Prevalence; Spinal Diseases
PubMed: 11718191
DOI: 10.1007/s005860100329 -
International Journal For Parasitology.... Dec 2019The free-living amebae Naegleria, Acanthamoeba, and Balamuthia cause rare but life-threatening infections. All three parasites can cause meningoencephalitis....
Identification of plicamycin, TG02, panobinostat, lestaurtinib, and GDC-0084 as promising compounds for the treatment of central nervous system infections caused by the free-living amebae Naegleria, Acanthamoeba and Balamuthia.
The free-living amebae Naegleria, Acanthamoeba, and Balamuthia cause rare but life-threatening infections. All three parasites can cause meningoencephalitis. Acanthamoeba can also cause chronic keratitis and both Balamuthia and Acanthamoeba can cause skin and systemic infections. There are minimal drug development pipelines for these pathogens despite a lack of available treatment regimens and high fatality rates. To identify anti-amebic drugs, we screened 159 compounds from a high-value repurposed library against trophozoites of the three amebae. Our efforts identified 38 compounds with activity against at least one ameba. Multiple drugs that bind the ATP-binding pocket of mTOR and PI3K are active, highlighting these compounds as important inhibitors of these parasites. Importantly, 24 active compounds have progressed at least to phase II clinical studies and overall 15 compounds were active against all three amebae. Based on central nervous system (CNS) penetration or exceptional potency against one amebic species, we identified sixteen priority compounds for the treatment of meningoencephalitis caused by these pathogens. The top five compounds are (i) plicamycin, active against all three free-living amebae and previously U.S. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis.
Topics: Acanthamoeba; Amebiasis; Amoebozoa; Antiprotozoal Agents; Carbazoles; Cell Culture Techniques; Central Nervous System Protozoal Infections; Culture Media; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Furans; Heterocyclic Compounds, 4 or More Rings; Inhibitory Concentration 50; Naegleria; Oxazines; Panobinostat; Plicamycin; Pyrimidines
PubMed: 31707263
DOI: 10.1016/j.ijpddr.2019.10.003 -
The American Journal of Pathology May 2004Fractalkine is an unusual tumor necrosis factor (TNF)-alpha-induced chemokine. The molecule is tethered to cells that express it and produces strong and direct adhesion...
Tumor necrosis factor-alpha induces fractalkine expression preferentially in arterial endothelial cells and mithramycin A suppresses TNF-alpha-induced fractalkine expression.
Fractalkine is an unusual tumor necrosis factor (TNF)-alpha-induced chemokine. The molecule is tethered to cells that express it and produces strong and direct adhesion to leukocytes expressing fractalkine receptor. However, the potential mechanism and significance of TNF-alpha-induced fractalkine expression in vascular endothelial cells are poorly understood. Here we show that in primary cultured endothelial cells TNF-alpha-induced fractalkine mRNA expression is mediated mainly through phosphatidylinositol 3'-kinase activation and nuclear factor (NF)-kappaB mediated transcriptional activation, along with GC-rich DNA-binding protein-mediated transcription. Interestingly, GC-rich DNA-binding protein inhibitors, mithramycin A and chromomycin A3, strongly suppressed TNF-alpha-induced fractalkine mRNA expression, possibly through inhibition of transcriptional activities by NF-kappaB and Sp1. In fact, direct inhibition of NF-kappaB and Sp1 bindings by decoy oligonucleotides suppressed TNF-alpha-induced fractalkine expression. Histologically, TNF-alpha-induced fractalkine expression was observed markedly in arterial and capillary endothelial cells, endocardium, and endothelium of intestinal villi, and slightly in venous endothelial cells, but not at all in lymphatic endothelial cells of intestine. Mithramycin A markedly suppressed TNF-alpha-induced fractalkine expression in vivo. These results indicate that TNF-alpha-stimulated fractalkine expression could act as part of arterial endothelial adhesion to leukocytes and monocytes during inflammation and atherosclerosis. NF-kappaB and Sp1 inhibitors such as mithramycin A may provide a pharmacological approach to suppressing these processes.
Topics: Animals; Arteries; Blotting, Western; Cell Line; Cell Line, Tumor; Cells, Cultured; Chemokine CX3CL1; Chemokines, CX3C; Densitometry; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Immunohistochemistry; Intestinal Mucosa; Male; Membrane Proteins; Myocardium; NF-kappa B; Oligonucleotides; Phosphatidylinositol 3-Kinases; Plicamycin; RNA, Messenger; Rats; Rats, Sprague-Dawley; Ribonucleases; Sp1 Transcription Factor; Time Factors; Transcriptional Activation; Tumor Necrosis Factor-alpha
PubMed: 15111313
DOI: 10.1016/s0002-9440(10)63725-x -
Molecular Pharmacology Aug 2019Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A...
Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: (multidrug resistance 3) rs2302387 and [bile salt export pump (BSEP)] rs4668115 reduce transporter expression ( < 0.05) and were associated with ≥grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day ×7, every 28 days; < 0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, sodium/taurocholate cotransporting polypeptide, organic solute transporter /) in several cell lines [Huh7, HepaRG, HepaRG BSEP (-/-)] and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes ( < 0.0001), and mithramycin inhibited chenodeoxycholic acid- and GW4046-induced FXR-galactose-induced gene 4 luciferase reporter activity ( < 0.001). Mithramycin promoted glycochenodeoxycholic acid-induced cytotoxicity in (--) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture ( < 0.01). Mithramycin is a FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a novel mechanism of drug-induced hepatotoxicity in which mithramycin not only alters farnesoid X receptor (FXR) and small heterodimer partner gene expression but also inhibits bile acid binding to FXR, resulting in deregulation of cellular bile homeostasis. Two novel single-nucleotide polymorphisms in bile flow transporters are associated with mithramycin-induced liver function test elevations, and the present results are the rationale for a genotype-directed clinical trial using mithramycin in patients with thoracic malignancies.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; Adult; Aged; Antibiotics, Antineoplastic; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase II as Topic; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Membrane Transport Proteins; Middle Aged; Plicamycin; Receptors, Cytoplasmic and Nuclear; Thoracic Neoplasms
PubMed: 31175181
DOI: 10.1124/mol.118.114827 -
Science Advances Apr 2024Histopathological heterogeneity is a hallmark of prostate cancer (PCa). Using spatial and parallel single-nucleus transcriptomics, we report an androgen receptor...
Histopathological heterogeneity is a hallmark of prostate cancer (PCa). Using spatial and parallel single-nucleus transcriptomics, we report an androgen receptor (AR)-positive but neuroendocrine-null primary PCa subtype with morphologic and molecular characteristics of small cell carcinoma. Such small cell-like PCa (SCLPC) is clinically aggressive with low AR, but high stemness and proliferation, activity. Molecular characterization prioritizes protein translation, represented by up-regulation of many ribosomal protein genes, and SP1, a transcriptional factor that drives SCLPC phenotype and overexpresses in castration-resistant PCa (CRPC), as two potential therapeutic targets in AR-indifferent CRPC. An SP1-specific inhibitor, plicamycin, effectively suppresses CRPC growth in vivo. Homoharringtonine, a Food And Drug Administration-approved translation elongation inhibitor, impedes CRPC progression in preclinical models and patients with CRPC. We construct an SCLPC-specific signature capable of stratifying patients for drug selectivity. Our studies reveal the existence of SCLPC in admixed PCa pathology, which may mediate tumor relapse, and establish SP1 and translation elongation as actionable therapeutic targets for CRPC.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Neoplasm Recurrence, Local; Transcription Factors; Protein Biosynthesis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38569039
DOI: 10.1126/sciadv.adm7098 -
Journal of Pharmacological Sciences 2013Mithramycin A (MTM) has been shown to inhibit cancer growth by blocking the binding of Sp-family transcription factors to gene regulatory elements and is used for the... (Review)
Review
Mithramycin A (MTM) has been shown to inhibit cancer growth by blocking the binding of Sp-family transcription factors to gene regulatory elements and is used for the treatment of leukemia and testicular cancer in the United States. In contrast, MTM has also been shown to exert neuroprotective effects in normal cells. An earlier study showed that MTM protected primary cortical neurons against oxidative stress-induced cell death. Recently, we demonstrated that MTM suppressed endoplasmic reticulum (ER) stress-induced neuronal death in organotypic hippocampal slice cultures and cultured hippocampal cells through attenuation of ER stress-associated signal proteins. We also found that MTM decreased neuronal death in area CA1 of the hippocampus after transient global ischemia/reperfusion in mice and restored the ischemia/reperfusion-induced impairment of long-term potentiation in this area. MTM has been shown to prolong the survival of Huntington's disease model mice and to attenuate dopaminergic neurotoxicity in mice after repeated administration of methamphetamine. In this review, we provide an up to date overview of neuroprotective effects of MTM and less toxic MTM analogs, MTM SK and MTM SDK, on some of the neurodegenerative diseases and discuss the promise of MTM as an agent for developing new therapeutic drugs for such diseases.
Topics: Animals; Cell Death; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Endoplasmic Reticulum Stress; Hippocampus; Humans; Huntington Disease; Long-Term Potentiation; Methamphetamine; Mice; Molecular Targeted Therapy; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Oxidative Stress; Plicamycin; Reperfusion Injury
PubMed: 23902990
DOI: 10.1254/jphs.13r02cp -
Advanced Science (Weinheim,... Nov 2023Although the MAPK/MEK/ERK pathway is prevalently activated in colorectal cancer (CRC), MEK/ERK inhibitors show limited efficiency in clinic. As a downstream target of...
Although the MAPK/MEK/ERK pathway is prevalently activated in colorectal cancer (CRC), MEK/ERK inhibitors show limited efficiency in clinic. As a downstream target of MAPK, ELK4 is thought to work primarily by forming a complex with SRF. Whether ELK4 can serve as a potential therapeutic target is unclear and the transcriptional regulatory mechanism has not been systemically analyzed. Here, it is shown that ELK4 promotes CRC tumorigenesis. Integrated genomics- and proteomics-based approaches identified SP1 and SP3, instead of SRF, as cooperative functional partners of ELK4 at genome-wide level in CRC. Serum-induced phosphorylation of ELK4 by MAPKs facilitated its interaction with SP1/SP3. The pathological neoangiogenic factor LRG1 is identified as a direct target of the ELK4-SP1/SP3 complex. Furthermore, targeting the ELK4-SP1/SP3 complex by combination treatment with MEK/ERK inhibitor and the relatively specific SP1 inhibitor mithramycin A (MMA) elicited a synergistic antitumor effect on CRC. Clinically, ELK4 is a marker of poor prognosis in CRC. A 9-gene prognostic model based on the ELK4-SP1/3 complex-regulated gene set showed robust prognostic accuracy. The results demonstrate that ELK4 cooperates with SP1 and SP3 to transcriptionally regulate LRG1 to promote CRC tumorigenesis in an SRF-independent manner, identifying the ELK4-SP1/SP3 complex as a potential target for rational combination therapy.
Topics: Humans; Promoter Regions, Genetic; Gene Expression Regulation; Colorectal Neoplasms; Carcinogenesis; Mitogen-Activated Protein Kinase Kinases; ets-Domain Protein Elk-4; Glycoproteins
PubMed: 37786278
DOI: 10.1002/advs.202303378 -
Cancer Research Aug 2012Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown....
Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell-related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Esophageal Neoplasms; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Proteins; Neoplastic Stem Cells; Plicamycin; Signal Transduction; Smoke; Tobacco Products; Xenograft Model Antitumor Assays
PubMed: 22751465
DOI: 10.1158/0008-5472.CAN-11-3983 -
Fertility and Sterility Jan 2021To determine the expression and functional roles of a long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) in leiomyoma.
OBJECTIVE
To determine the expression and functional roles of a long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) in leiomyoma.
DESIGN
Experimental study.
SETTING
Academic research laboratory.
PATIENT(S)
Women undergoing hysterectomy for leiomyoma.
INTERVENTION(S)
Overexpression and underexpression of XIST; blockade of specific protein 1 (SP1).
MAIN OUTCOME MEASURE(S)
Expression of XIST in leiomyoma and its effects on microRNA 29c (miR-29c), miR-200c, and their targets.
RESULT(S)
Leiomyoma expressed statistically significantly more XIST as compared with matched myometrium, independent of race/ethnicity and menstrual cycle phase. By use of a three-dimensional spheroid culture system, we found reduced XIST levels in leiomyoma smooth muscle cells (LSMC) after treatment with 17β-estradiol, progesterone, and their combination. The expression of XIST was down-regulated by treatment with the SP1-inhibitor mithramycin A and SP1 small interfering RNA. Knockdown of XIST resulted in inhibition of cell proliferation, up-regulation of miR-29c and miR-200c, and a concomitant inhibition of the target genes of these miRNAs, namely collagen type I (COL1A1), collagen type III (COL3A1), and fibronectin (FN1). By contrast, overexpression of XIST in myometrium smooth muscle cells repressed miR-29c and miR-200c, and induced COL1A1, COL3A1, and FN1 levels. By use of RNA immunoprecipitation analysis we confirmed XIST has sponge activity over miR-29c and miR-200c, which is more pronounced in leiomyoma as compared with myometrium.
CONCLUSION(S)
Our data demonstrate that increased expression of XIST in leiomyoma results in reduced expression of miR-29c and miR-200c with a consequent up-regulation of the genes targeted by these microRNAs including COL1A1, COL3A1, and FN1, which play key roles in extracellular matrix accumulation associated with fibroids.
Topics: Adult; Cell Proliferation; Cells, Cultured; Female; Gene Expression Regulation, Neoplastic; Humans; Leiomyoma; Middle Aged; Myocytes, Smooth Muscle; Myometrium; Primary Cell Culture; RNA, Long Noncoding; Uterine Neoplasms
PubMed: 33070965
DOI: 10.1016/j.fertnstert.2020.07.024