-
Cancer Medicine Dec 2018AU-rich elements (ARE) exist in the 3'-untranslated regions of the mRNA transcribed from cell growth-related genes such as proto-oncogenes, cyclin-related genes, and...
AU-rich elements (ARE) exist in the 3'-untranslated regions of the mRNA transcribed from cell growth-related genes such as proto-oncogenes, cyclin-related genes, and growth factors. HuR binds and stabilizes ARE-mRNA. HuR is expressed abundantly in cancer cells and related malignant phenotypes. HuR knockdown attenuates the malignant phenotype of oral cancer cells. In this study, we screened 1570 compounds in the approved drug library by differential scanning fluorimetry (DSF) to discover a HuR-targeted compound. Firstly, 55 compounds were selected by DSF. Then, 8 compounds that showed a shift in the melting temperature value in a concentration-dependent manner were selected by DSF. Of them, suramin, an anti-trypanosomal drug, binds to HuR, exhibiting fast-on and fast-off kinetic behavior on surface plasmon resonance (SPR). We confirmed that suramin significantly decreased mRNA and protein expression of cyclin A2 and cyclin B1. The cyclin A2 and cyclin B1 mRNAs were destabilized by suramin. Furthermore, the motile and invasive activities of a tongue carcinoma cell line treated with suramin were markedly lower than those of control cells. The above findings suggest that suramin binds to HuR and inhibits its function. We also showed that the anticancer effects of suramin were caused by the inhibition of HuR function, indicating its potential as a novel therapeutic agent in the treatment of oral cancer. Our results suggest that suramin, via its different mechanism, may effectively suppress progressive oral cancer that cannot be controlled using other anticancer agents.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Survival; ELAV-Like Protein 1; Humans; Small Molecule Libraries; Suramin; Tongue Neoplasms; Wound Healing
PubMed: 30449075
DOI: 10.1002/cam4.1877 -
International Journal of Cancer Oct 2007Rapid tumor growth and metastasis are 2 major problems associated with treatment of malignant melanoma. Therefore, drugs that can intervene these processes are of...
Rapid tumor growth and metastasis are 2 major problems associated with treatment of malignant melanoma. Therefore, drugs that can intervene these processes are of clinical importance. Pentoxifylline (PTX), a methyl xanthine derivative, has been shown to inhibit B16F10 melanoma tumor growth and metastasis. We hypothesized that suramin when combined with PTX enhances its antineoplastic effects, which we have examined using the B16F10 mouse melanoma model. Suramin in simultaneous or sequential combination potentiated the cytotoxic effects of PTX on B16F10 cells. PTX arrested cells in the G0-G1 phase and suramin augmented the effects. Both the drugs inhibited F10 adhesion to laminin, matrigel and collagen type IV and showed enhanced inhibition in combination The combination also demonstrated significantly higher inhibition in cell motility (p = 0.002) and invasion through matrigel (p = 0.005) as compared to the single agents. Suramin synergized with PTX in its effects on secretion of MMP-9 gelatinase. DBA2/J mice implanted with intradermal B16F10 tumor were used as a model to study tumor growth. Animals were intratumorally treated with 50 mg/kg of PTX, 10 mg/kg of suramin and their combinations. Simultaneous administration of the drugs inhibited tumor growth by 5- to 6-folds. Tumor growth was completely blocked in sequential regimen with regression in some cases. The number and size of metastatic nodules on lung was also reduced significantly by the combination treatment. In conclusion, the novel combination of PTX and suramin has synergistic antitumor and antimetastatic activity in B16F10 melanoma and may be a promising approach in treatment of patients suffering from malignant melanoma.
Topics: Analysis of Variance; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Adhesion; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Survival; Collagen; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Extracellular Matrix; Laminin; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; NIH 3T3 Cells; Pentoxifylline; Proteoglycans; Suramin; Time Factors
PubMed: 17582610
DOI: 10.1002/ijc.22843 -
Journal of Diabetes Investigation Feb 2023Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes produce IL-18 upon being activated by various stimuli via...
AIMS/INTRODUCTION
Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes produce IL-18 upon being activated by various stimuli via the P2 receptors. Previously, we showed that serum and urine IL-18 levels are positively associated with albuminuria in patients with type 2 diabetes, indicating the involvement of inflammasome activation in the pathogenesis of diabetic kidney disease (DKD). In the present study, we investigated whether the administration of suramin, a nonselective antagonist of the P2 receptors, protects diabetic KK.Cg-A /TaJcl (KK-Ay) mice against DKD progression.
MATERIALS AND METHODS
Suramin or saline was administered i.p. to KK-Ay and C57BL/6J mice once every 2 weeks for a period of 8 weeks. Mouse mesangial cells (MMCs) were stimulated with ATP in the presence or absence of suramin.
RESULTS
Suramin treatment significantly suppressed the increase in the urinary albumin-to-creatinine ratio, glomerular hypertrophy, mesangial matrix expansion, and glomerular fibrosis in KK-Ay mice. Suramin also suppressed the upregulation of NLRP3 inflammasome-related genes and proteins in the renal cortex of KK-Ay mice. P2X4 and P2X7 receptors were significantly upregulated in the isolated glomeruli of KK-Ay mice and mainly distributed in the glomerular mesangial cells of KK-Ay mice. Although neither ATP nor suramin affected NLRP3 expression in MMCs, suramin inhibited ATP-induced NLRP3 complex formation and the downstream expression of caspase-1 and IL-18 in MMCs.
CONCLUSIONS
These results suggest that the NLRP3 inflammasome is activated in a diabetic kidney and that inhibition of the NLRP3 inflammasome with suramin protects against the progression of early stage DKD.
Topics: Mice; Animals; Diabetic Nephropathies; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Interleukin-18; Suramin; Diabetes Mellitus, Type 2; Mice, Inbred C57BL; Adenosine Triphosphate
PubMed: 36308062
DOI: 10.1111/jdi.13930 -
The AAPS Journal Dec 2010Suramin, at non-cytotoxic doses, reverses chemoresistance and enhances the activity of mitomycin C (MMC) in mice bearing human bladder xenograft tumors. The present...
Suramin, at non-cytotoxic doses, reverses chemoresistance and enhances the activity of mitomycin C (MMC) in mice bearing human bladder xenograft tumors. The present study evaluated the pharmacokinetics of the intravesical suramin and MMC, alone or in combination, in dogs. Animals received either high dose suramin (20 mg/ml), low dose suramin (6 mg/ml), MMC (2 mg/ml), or combination of low dose suramin and MMC, instilled for 2 h. The dosing volume was 20 ml. All groups showed dilution of drug levels over time due to continued urine production. For single agent suramin, the results showed (a) 5% to 10% penetration into bladder tissues, (b) minimal and clinically insignificant systemic absorption (i.e., undetectable at low dose or a peak concentration that was 6,000× lower than urine concentrations), and (c) disproportionally higher drug penetration and concentrations in bladder tissues at the higher dose. Results for single agent MMC are consistent with our earlier observations. The co-administration of MMC did not alter the plasma, urine, or tissue pharmacokinetics of suramin. Adding suramin did not alter plasma or tissue pharmacokinetics of MMC, but lowered the MMC concentrations in urine by about 20%. This may be in part due to accelerated MMC degradation by co-incubation of suramin or due to variations in urine production rate (because animals were allowed for water during treatment). Suramin readily penetrates the urothelium and into deeper bladder tissues, indicating its potential utility in intravesical therapy.
Topics: Animals; Antineoplastic Agents; Dogs; Female; Male; Mitomycin; Suramin; Urinary Bladder
PubMed: 20625863
DOI: 10.1208/s12248-010-9219-8 -
Scientific Reports Jul 2018Local myonecrosis is the main event resulting from snakebite envenomation by the Bothrops genus and, frequently, it is not efficiently neutralized by antivenom...
Local myonecrosis is the main event resulting from snakebite envenomation by the Bothrops genus and, frequently, it is not efficiently neutralized by antivenom administration. Proteases, phospholipases A (PLA) and PLA-like toxins are found in venom related to muscle damage. Functional sites responsible for PLA-like toxins activity have been proposed recently; they consist of a membrane docking-site and a membrane rupture-site. Herein, a combination of functional, biophysical and crystallographic techniques was used to characterize the interaction between suramin and MjTX-I (a PLA-like toxin from Bothrops moojeni venom). Functional in vitro neuromuscular assays were performed to study the biological effects of the protein-ligand interaction, demonstrating that suramin neutralizes the myotoxic effect of MjTX-I. Calorimetric assays showed two different binding events: (i) inhibitor-protein interactions and (ii) toxin oligomerization processes. These hypotheses were also corroborated with dynamic light and small angle X-ray scattering assays. The crystal structure of the MjTX-I/suramin showed a totally different interaction mode compared to other PLA-like/suramin complexes. Thus, we suggested a novel myotoxic mechanism for MjTX-I that may be inhibited by suramin. These results can further contribute to the search for inhibitors that will efficiently counteract local myonecrosis in order to be used as an adjuvant of conventional serum therapy.
Topics: Animals; Binding Sites; Bothrops; Crotalid Venoms; Crystallography, X-Ray; Molecular Dynamics Simulation; Phospholipases A2; Protein Structure, Quaternary; Reptilian Proteins; Scattering, Small Angle; Suramin; Thermodynamics
PubMed: 29985425
DOI: 10.1038/s41598-018-28584-7 -
The Journal of Biological Chemistry May 1991Suramin, a polysulfonated naphthylurea, has anti-reverse transcriptase and anti-proliferative activities and inhibits the binding of various growth factors to their cell...
Suramin, a polysulfonated naphthylurea, has anti-reverse transcriptase and anti-proliferative activities and inhibits the binding of various growth factors to their cell surface receptors. This drug is used in the treatment of acquired immunodeficiency syndrome and several types of cancers. Increased levels of circulating glycosaminoglycans have been observed in suramin-treated cancer patients, suggesting that it may inhibit glycosaminoglycan catabolism. Melanoma-derived heparanase, a heparan sulfate-specific endo-beta-D-glucuronidase that plays an important role in metastatic melanoma cell invasion through basement membranes, is inhibited by suramin in a dose-dependent manner: 100% inhibition was observed at a concentration of approximately 100 microM. Structurally related polysulfonated compounds, such as trypan blue and Evans blue, had lower heparanase inhibitory activities: the concentrations required for 50% heparanase inhibition (ID50) were 310-320 microM and six times higher than for suramin (ID50 = 46 microM). Oversulfated heparin tetrasaccharide, whose average molecular size is similar to suramin, had also much lower heparanase inhibitory activity than suramin. The inhibition constants (Ki) for suramin and oversulfated heparin tetrasaccharide were 48 and 290 microM, respectively. Suramin had a remarkable inhibitory activity against B16 melanoma cell invasion through reconstituted basement membranes (ID50 less than 10 microM). The inhibitory effects of suramin on melanoma heparanase and cell invasion appeared to be completely independent of its antiproliferative activity, because significant effects on melanoma cell growth were not observed at the concentrations of suramin used in this study. The results suggest that the antimetastatic effects of suramin may be due to its antiinvasive rather than antiproliferative activities.
Topics: Animals; Antineoplastic Agents; Chromatography, Gel; Extracellular Matrix; Glucuronidase; Glycoside Hydrolases; Kinetics; Melanoma, Experimental; Mice; Rats; Suramin; Tumor Cells, Cultured
PubMed: 2033058
DOI: No ID Found -
Proceedings of the National Academy of... Apr 2016Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity...
Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3's cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a small-molecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1's conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2-E3 interface through small-molecule modulators.
Topics: Ligases; Structure-Activity Relationship; Suramin
PubMed: 27001857
DOI: 10.1073/pnas.1601089113 -
Antiviral Research Oct 2016The chikungunya virus (CHIKV), an arthritogenic alphavirus, has caused explosive epidemics involving millions of cases. Globally expanding pandemics involving CHIKV and...
The chikungunya virus (CHIKV), an arthritogenic alphavirus, has caused explosive epidemics involving millions of cases. Globally expanding pandemics involving CHIKV and post-CHIKV rheumatic disorders are increasing public health concerns. However, no antiviral interventions or vaccines to control CHIKV infection have yet been approved. Although suramin has been possess anti-CHIKV activity in vitro, whether suramin has anti-CHIKV activity in vivo remains unknown. This study aimed to determine whether suramin treatment could ameliorate CHIKV-induced arthritis in a C57BL/6 mice model. C57BL/6 mice were infected with CHIKVs to evaluate anti-CHIKV activities of suramin in terms of histopathology, viral burden and disease score. Not only did suramin treatment substantially decrease viral loads, but it also significantly ameliorated acute foot lesions in mice. In addition, suramin treatment markedly restores cartilage integrity and reduces the number of IHC positive chondrocyte in mice infected with CHIKV strains 0810bTw and 0706aTw. This in vivo study highlights the potential ability of suramin to treat CHIKV infection in clinical settings.
Topics: Animals; Antiviral Agents; Chikungunya Fever; Chikungunya virus; Disease Models, Animal; Foot; Mice; Mice, Inbred C57BL; Musculoskeletal Diseases; Suramin; Viral Load; Virus Replication
PubMed: 27577529
DOI: 10.1016/j.antiviral.2016.07.025 -
Journal of the American Society of... Jun 2011The activation of cytokine and growth factor receptors associates with the development and progression of renal fibrosis. Suramin is a compound that inhibits the...
The activation of cytokine and growth factor receptors associates with the development and progression of renal fibrosis. Suramin is a compound that inhibits the interaction of several cytokines and growth factors with their receptors, but whether suramin inhibits the progression of renal fibrosis is unknown. Here, treatment of cultured renal interstitial fibroblasts with suramin inhibited their activation induced by TGF-β1 and serum. In a mouse model of obstructive nephropathy, administration of a single dose of suramin immediately after ureteral obstruction abolished the expression of fibronectin, largely suppressed expression of α-SMA and type I collagen, and reduced the deposition of extracellular matrix proteins. Suramin also decreased the expression of multiple cytokines including TGF-β1 and reduced the interstitial infiltration of leukocytes. Moreover, suramin decreased expression of the type II TGF-β receptor, blocked phosphorylation of the EGF and PDGF receptors, and inactivated several signaling pathways associated with the progression of renal fibrosis. In a rat model of CKD, suramin abrogated proteinuria, limited the decline of renal function, and prevented glomerular and tubulointerstitial damage. Collectively, these findings indicate that suramin is a potent antifibrotic agent that may have therapeutic potential for patients with fibrotic kidney diseases.
Topics: Actins; Animals; Antineoplastic Agents; Cells, Cultured; Chronic Disease; Disease Models, Animal; Disease Progression; Fibroblasts; Fibronectins; Fibrosis; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Proteinuria; Rats; Rats, Sprague-Dawley; Smad Proteins; Suramin; Transforming Growth Factor beta1; Treatment Outcome
PubMed: 21617121
DOI: 10.1681/ASN.2010090956 -
Scientific Reports Mar 2023Tau is an intrinsically disordered neuronal protein in the central nervous system. Aggregated Tau is the main component of neurofibrillary tangles observed in...
Tau is an intrinsically disordered neuronal protein in the central nervous system. Aggregated Tau is the main component of neurofibrillary tangles observed in Alzheimer's disease. In vitro, Tau aggregation can be triggered by polyanionic co-factors, like RNA or heparin. At different concentration ratios, the same polyanions can induce Tau condensates via liquid-liquid phase separation (LLPS), which over time develop pathological aggregation seeding potential. Data obtained by time resolved Dynamic Light Scattering experiments (trDLS), light and electron microscopy show that intermolecular electrostatic interactions between Tau and the negatively charged drug suramin induce Tau condensation and compete with the interactions driving and stabilizing the formation of Tau:heparin and Tau:RNA coacervates, thus, reducing their potential to induce cellular Tau aggregation. Tau:suramin condensates do not seed Tau aggregation in a HEK cell model for Tau aggregation, even after extended incubation. These observations indicate that electrostatically driven Tau condensation can occur without pathological aggregation when initiated by small anionic molecules. Our results provide a novel avenue for therapeutic intervention of aberrant Tau phase separation, utilizing small anionic compounds.
Topics: Humans; tau Proteins; Suramin; Alzheimer Disease; Heparin; RNA
PubMed: 36894559
DOI: 10.1038/s41598-023-29846-9