Anticancer drug mithramycin interacts with core histones: An additional mode of action of the DNA groove binder

Banerjee, Amrita; Sanyal, Sulagna; Kulkarni, Kirti; Jana, Kuladip; Roy, Siddhartha; Das, Chandrima; Dasgupta, Dipak

doi:10.1016/j.fob.2014.10.007

Cited by 11 publications

(7 citation statements)

References 56 publications

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“…A solution (DNA‐EB) containing DNA (100 μ m ) and EB (10 μ m ) was made in buffer, 5 m m Tris–HCl/50 m m NaCl (pH = 7.2). The fluorescence emission spectra were recorded at λ ex 490 nm for solutions of varying concentrations (5, 10, 15, 20, 25, 30, 35 and 40 μ m ) of compounds ( S ) ‐L 1 H , ( S ) ‐L 2 H , ( S ) ‐1 and ( S ) ‐2 in the presence of DNA‐EB after incubation of these solutions at RT for 10 min 48a–d . The emission spectra obtained in the absence and presence of increasing amounts of the above compounds are shown in Figure 6.…”

Section: Resultsmentioning

confidence: 99%

“…However, the fluorescence emission spectra of these compounds showed that there was no appreciable change of emission intensity of DNA‐EB with increasing concentrations, indicating a non‐intercalative mode of interaction with CT‐DNA 15f . The fluorescence quenching capability of these compounds was evaluated from Stern–Volmer constant, K sv , which was determined using the following equation: 48

I_{O} / I = 1 + K_{sv} ([], M)

where I O and I correspond to the fluorescence intensities in the absence and presence of compounds respectively, [ M ] is the concentration of compounds (quenching agent, Q) and K sv is the linear Stern‐Volmer constant. A graph for I O / I against [ M ] for each of these compounds is shown in the inset of Figure 6.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis, characterization, CT‐DNA binding and docking studies of novel selenated ligands and their palladium complexes

Kumar

et al. 2020

Applied Organom Chemis

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A novel selenated Schiff base (S)‐L1H has been synthesized from (2S)‐1‐(benzylselanyl)‐3‐phenylpropan‐2‐amine which upon reduction formed a reduced Schiff base (S)‐L2H. Palladium (II) complexes (S)‐1 and (S)‐2 of ligands (S)‐L1H and (S)‐L2H respectively were successfully synthesized. The structures of all four compounds were thoroughly identified by analytical and various spectroscopic techniques. The absolute molecular structures of the above two complexes were further confirmed by single crystal X‐ray diffraction. Both (S)‐L1H and (S)‐L2H coordinated as monobasic ((S)‐L1–2), chelating, tridentate (Se,N,O−) ligands resulting in the complexes of composition (S)‐[PdCl(L1/2)] [(S)‐1/2]. In the crystals of complexes (S)‐1 and (S)‐2, there were moderate to strong Se⋯O, CH⋯Cl and CH⋯O types of intermolecular secondary interactions. CT‐DNA binding activity of these selenium‐containing ligands and their palladium complexes bearing a Pd–Se bond have been evaluated for the first time by performing electronic absorption titration and fluorescence emission quenching using CT‐DNA‐EB and viscometric experiments. These ligands and complexes exhibited remarkable DNA binding activity as shown by their intrinsic DNA binding constants (Kb) and Stern–Volmer constants (Ksv) in the ranges 5.2–9.9 × 104 and 3.6–4.7 × 104, respectively. The viscosity of CT‐DNA decreases with increasing concentration of these compounds. The results of the DNA‐binding studies revealed that all of the compounds interact with DNA at a minor groove which was further confirmed by molecular docking studies.

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Section: Resultsmentioning

confidence: 99%

I_{O} / I = 1 + K_{sv} ([], M)

Section: Resultsmentioning

confidence: 99%

Synthesis, characterization, CT‐DNA binding and docking studies of novel selenated ligands and their palladium complexes

Kumar

et al. 2020

Applied Organom Chemis

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“…Several reports have shown SP1-independent gene expression after MitA treatment [ 46 , 47 ]. By examining OA-associated genes and signaling pathways, we identified HIF-2α as a factor specifically down-regulated by MitA.…”

Section: Discussionmentioning

confidence: 99%

“…Another possibility is that MitA can regulate histone modifications, resulting in dysregulation of NF-κB activation. Besides DNA, MitA can also bind to core histones present in chromatin and inhibit histone H3 acetylation to regulate gene expressions [ 47 ]. Moreover, MitA can inhibit a subset of class I histone deacetylase expression [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Mithramycin A Alleviates Osteoarthritic Cartilage Destruction by Inhibiting HIF-2α Expression

Choi

2018

IJMS

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Osteoarthritis (OA) is the most common and increasing joint disease worldwide. Current treatment for OA is limited to control of symptoms. The purpose of this study was to determine the effect of specificity protein 1 (SP1) inhibitor Mithramycin A (MitA) on chondrocyte catabolism and OA pathogenesis and to explore the underlying molecular mechanisms involving SP1 and other key factors that are critical for OA. Here, we show that MitA markedly inhibited expressions of matrix-degrading enzymes induced by pro-inflammatory cytokine interleukin-1β (IL-1β) in mouse primary chondrocytes. Intra-articular injection of MitA into mouse knee joint alleviated OA cartilage destruction induced by surgical destabilization of the medial meniscus (DMM). However, modulation of SP1 level in chondrocyte and mouse cartilage did not alter catabolic gene expression or cartilage integrity, respectively. Instead, MitA significantly impaired the expression of HIF-2α known to be critical for OA pathogenesis. Such reduction in expression of HIF-2α by MitA was caused by inhibition of NF-κB activation, at least in part. These results suggest that MitA can alleviate OA pathogenesis by suppressing NF-κB-HIF-2α pathway, thus providing insight into therapeutic strategy for OA.

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“…The fact that combined SP1 knockdown/p53 over-expression did not fully recapitulate growth inhibition and gene expression profiles observed in MM-treated MPM cells suggests that additional as yet uncharacterized mechanisms contribute to MM-mediated cell cycle arrest, senescence and apoptosis in MPM cells. For example, recently described interactions of MM with core histones could account, in part, for repression of genes lacking prototypic SP1 or p53 recognition elements within their respective promoters {Banerjee, 2014 3218 /id}. Experiments are underway to examine these issues, and to ascertain if small molecule mdm2-p53 inhibitors {Zhang, 2015 3222 /id} or agents which inhibit p21 expression {Nguyen, 2004 1774 /id} can augment MM-mediated apoptosis in MPM cells.…”

Section: Discussionmentioning

confidence: 99%

Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells

Rao

Atay

Shukla

et al. 2016

Clinical Cancer Research

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Purpose Specificity protein 1 (SP1) is an oncogenic transcription factor over-expressed in various human malignancies. This study sought to examine SP1 expression in malignant pleural mesotheliomas (MPM), and ascertain the potential efficacy of targeting SP1 in these neoplasms. Experimental Design qRT-PCR, immunoblot and immunohistochemistry techniques were used to evaluate SP1 expression in cultured MPM cells and MPM specimens and normal mesothelial cells/pleura. MTS, chemotaxis, soft agar, ß-galactosidase and Apo-BrdU techniques were used to assess proliferation, migration, clonogenicity, senescence and apoptosis in MPM cells following SP1 knockdown, p53 over-expression, or mithramycin treatment. Murine subcutaneous and intraperitoneal (IP) xenograft models were used to examine effects of mithramycin on MPM growth in vivo. Microarray, qRT-PCR, immunoblot and chromatin immunoprecipitation techniques were used to examine gene expression profiles mediated by mithramycin and combined SP1 knockdown/p53 over-expression, and correlate these changes with SP1 and p53 levels within target gene promoters. Results MPM cells and tumors exhibited higher SP1 mRNA and protein levels relative to control cells/tissues. SP1 knockdown significantly inhibited proliferation, migration and clonogenicity of MPM cells. Mithramycin depleted SP1 and activated p53, dramatically inhibiting proliferation and clonogenicity of MPM cells. IP mithramycin significantly inhibited growth of subcutaneous MPM xenografts, and completely eradicated mesothelioma carcinomatosis in 75% of mice. Mithramycin modulated genes mediating oncogene signaling, cell cycle regulation, senescence and apoptosis in-vitro and in-vivo. The growth inhibitory effects of mithramycin in MPM cells were recapitulated by combined SP1 knockdown/p53 overexpression. Conclusions These findings provide preclinical rationale for phase II evaluation of mithramycin in mesothelioma patients.

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Anticancer drug mithramycin interacts with core histones: An additional mode of action of the DNA groove binder

Abstract: HighlightsMithramycin (MTR) binds to core histones but not to linker histone H1.Unlike MTR–DNA interaction, MTR–histone association is metal independent.MTR alters H3K18 acetylation in vitro and ex vivo.MTR is a dual binder (binds to both DNA and histones) in the chromatin context.

Cited by 11 publications

References 56 publications

Synthesis, characterization, CT‐DNA binding and docking studies of novel selenated ligands and their palladium complexes

Synthesis, characterization, CT‐DNA binding and docking studies of novel selenated ligands and their palladium complexes

Mithramycin A Alleviates Osteoarthritic Cartilage Destruction by Inhibiting HIF-2α Expression

Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells

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