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PloS One 2012The anticancer activity of DNA intercalators is related to their ability to intercalate into the DNA duplex with high affinity, thereby interfering with DNA replication...
The anticancer activity of DNA intercalators is related to their ability to intercalate into the DNA duplex with high affinity, thereby interfering with DNA replication and transcription. Polyamines (spermine in particular) are almost exclusively bound to nucleic acids and are involved in many cellular processes that require nucleic acids. Until now, the effects of polyamines on DNA intercalator activities have remained unclear because intercalation is the most important mechanism employed by DNA-binding drugs. Herein, using actinomycin D (ACTD) as a model, we have attempted to elucidate the effects of spermine on the action of ACTD, including its DNA-binding ability, RNA and DNA polymerase interference, and its role in the transcription and replication inhibition of ACTD within cells. We found that spermine interfered with the binding and stabilization of ACTD to DNA. The presence of increasing concentrations of spermine enhanced the transcriptional and replication activities of RNA and DNA polymerases, respectively, in vitro treated with ActD. Moreover, a decrease in intracellular polyamine concentrations stimulated by methylglyoxal-bis(guanylhydrazone) (MGBG) enhanced the ACTD-induced inhibition of c-myc transcription and DNA replication in several cancer cell lines. The results indicated that spermine attenuates ACTD binding to DNA and its inhibition of transcription and DNA replication both in vitro and within cells. Finally, a synergistic antiproliferative effect of MGBG and ACTD was observed in a cell viability assay. Our findings will be of significant relevance to future developments in combination with cancer therapy by enhancing the anticancer activity of DNA interactors through polyamine depletion.
Topics: Antineoplastic Agents; Bacteriophage T7; Cell Line, Tumor; DNA; DNA Polymerase I; DNA Replication; DNA-Directed RNA Polymerases; Dactinomycin; Escherichia coli; Humans; Intercalating Agents; Mitoguazone; Models, Molecular; Neoplasms; Spermine; Transcription, Genetic
PubMed: 23144800
DOI: 10.1371/journal.pone.0047101 -
Chemical & Pharmaceutical Bulletin 2016Chondroitin sulfate (CS) has been accepted as an ingredient in health foods for the treatment of symptoms related to arthritis and cartilage repair. However, CS is...
Chondroitin sulfate (CS) has been accepted as an ingredient in health foods for the treatment of symptoms related to arthritis and cartilage repair. However, CS is poorly absorbed through the gastrointestinal tract because of its high negative electric charges and molecular weight (MW). In this study, poly-ion complex (PIC) formation was found in aqueous solutions through electrostatic interaction between CS and polyamines-organic molecules having two or more primary amino groups ubiquitously distributed in natural products at high concentrations. Characteristic properties of various PICs generated by mixing CS and natural polyamines, including unusual polyamines, were studied based on the turbidity for PIC formation, the dynamic light scattering for the size of PIC particles, and ζ-potential measurements for the surface charges of PIC particles. The efficiency of PIC formation between CS and spermine increased in a CS MW-dependent manner, with 15 kDa CS being critical for the formation of PIC (particle size: 3.41 µm) having nearly neutral surface charge (ζ-potential: -0.80 mV). Comparatively, mixing tetrakis(3-aminopropyl)ammonium and 15 kDa of CS afforded significant levels of PIC (particle size: 0.42±0.16 µm) despite a strongly negative surface charge (-34.67±1.15 mV). Interestingly, the oral absorption efficiency of CS was greatly improved only when PIC possessing neutral surface charges was administered to mice. High formation efficiency and electrically neutral surface charge of PIC particles are important factors for oral CS bioavailability.
Topics: Administration, Oral; Animals; Biological Availability; Chondroitin Sulfates; Female; Mice; Mice, Inbred Strains; Molecular Structure; Particle Size; Spermine; Static Electricity; Surface Properties
PubMed: 27150471
DOI: 10.1248/cpb.c15-00940 -
(,)-1,12-Dimethylspermine can mitigate abnormal spermidine accumulation in Snyder-Robinson syndrome.The Journal of Biological Chemistry Mar 2020Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome caused by a loss-of-function mutation in the spermine synthase () gene. Primarily...
Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome caused by a loss-of-function mutation in the spermine synthase () gene. Primarily affecting males, the main manifestations of SRS include osteoporosis, hypotonic stature, seizures, cognitive impairment, and developmental delay. Because there is no cure for SRS, treatment plans focus on alleviating symptoms rather than targeting the underlying causes. Biochemically, the cells of individuals with SRS accumulate excess spermidine, whereas spermine levels are reduced. We recently demonstrated that SRS patient-derived lymphoblastoid cells are capable of transporting exogenous spermine and its analogs into the cell and, in response, decreasing excess spermidine pools to normal levels. However, dietary supplementation of spermine does not appear to benefit SRS patients or mouse models. Here, we investigated the potential use of a metabolically stable spermine mimetic, (,)-1,12-dimethylspermine (MeSPM), to reduce the intracellular spermidine pools of SRS patient-derived cells. MeSPM can functionally substitute for the native polyamines in supporting cell growth while stimulating polyamine homeostatic control mechanisms. We found that both lymphoblasts and fibroblasts from SRS patients can accumulate MeSPM, resulting in significantly decreased spermidine levels with no adverse effects on growth. MeSPM administration to mice revealed that MeSPM significantly decreases spermidine levels in multiple tissues. Importantly, MeSPM was detectable in brain tissue, the organ most affected in SRS, and was associated with changes in polyamine metabolic enzymes. These findings indicate that the (,)-diastereomer of 1,12-MeSPM represents a promising lead compound in developing a treatment aimed at targeting the molecular mechanisms underlying SRS pathology.
Topics: Acetyltransferases; Animals; Brain; Chromatography, High Pressure Liquid; Fibroblasts; Humans; Male; Mental Retardation, X-Linked; Mice; Mice, Inbred C57BL; Polyamines; Spermidine; Spermine; Spermine Synthase; Tumor Cells, Cultured
PubMed: 31996374
DOI: 10.1074/jbc.RA119.011572 -
Molecules (Basel, Switzerland) Apr 2022Conformationally restrained polyamine analog PG11047 is a well-known drug candidate that modulates polyamine metabolism and inhibits cancer cell growth in a broad...
Conformationally restrained polyamine analog PG11047 is a well-known drug candidate that modulates polyamine metabolism and inhibits cancer cell growth in a broad spectrum of cancers. Here, we report a structure-activity relationship study of the PG11047 analogs (HPGs) containing alkyl chains of varying length, while keeping the unsaturated spermine backbone unchanged. Synthesis of higher symmetrical homologues was achieved through a synthetic route with fewer steps than the previous route to PG11047. The amphiphilic HPG analogs underwent self-assembly and formed spherically shaped nanoparticles whose size increased with the hydrophobic alkyl group's increasing chain length. Assessment of the in vitro anticancer activity showed more than an eight-fold increase in the cancer cell inhibition activity of the analogs with longer alkyl chains compared to PG11047 in human colon cancer cell line HCT116, and a more than ten-fold increase in human lung cancer cell line A549. Evaluation of the inhibition of spermine oxidase (SMOX) showed no activity for PG11047, but activity was observed for its higher symmetrical homologues. Comparison with a reference SMOX inhibitor MDL72527 showed nine-fold better activity for the best performing HPG analog.
Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Lung Neoplasms; Nanoparticles; Polyamines; Spermine
PubMed: 35458639
DOI: 10.3390/molecules27082441 -
Microbiology Spectrum Jan 2024This is the first study that attempted to demonstrate the mechanisms of reactive oxygen species (ROS) generation by spermine (Spm) in (M.tb). Furthermore, this is the...
This is the first study that attempted to demonstrate the mechanisms of reactive oxygen species (ROS) generation by spermine (Spm) in (M.tb). Furthermore, this is the first study to demonstrate that it is able to enhance the activity of currently available and World Health Organization (WHO)-approved tuberculosis (TB) drugs. Spermine can easily be obtained since it is already found in our diet. Moreover, as opposed to conventional antibiotics, it is less toxic to humans since it is found in millimolar concentrations in the body. Finally, with the difficulty of curing TB with conventional antibiotics, this study suggests that less toxic molecules, such as Spm, could in a long-term perspective be incorporated in a TB regimen to boost the treatment.
Topics: Humans; Antitubercular Agents; Spermine; Isoniazid; Rifampin; Tuberculosis; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Microbial Sensitivity Tests
PubMed: 38095461
DOI: 10.1128/spectrum.03568-23 -
Scientific Reports Jan 2023In this study, aqueous spinach extract was used for the green synthesis of iron nanoparticles. The surface of iron oxide nanoparticles was coated with spermine. The...
In this study, aqueous spinach extract was used for the green synthesis of iron nanoparticles. The surface of iron oxide nanoparticles was coated with spermine. The physicochemical properties of nanoparticles were investigated using UV-Vis, TGA, FTIR, VSM, TEM, and DLS. The results showed that the nanoparticles had a spherical structure. The surface charge of the FeO-NPs increased from -3.2 to 18.42 (mV) after FeO coating by spermine. In order to investigate the effect of nanoparticles on physicochemical properties of rosemary under drought stress conditions, an experiment was carried out in a completely randomized design. The results showed that the amount of antioxidant enzymes and secondary metabolites increased significantly under drought stress. Moreover, the use of spermine-coated iron nanoparticles can be useful in increasing resistance to drought stress in plants by increasing the activity of some antioxidant enzymes and secondary metabolites. The biocompatibility of Nanoparticles in cell suspension was investigated. the ability of FeO-SM NPs to interact with DNA and protect it against DNaseI and ultrasonic waves using agarose gel electrophoresis was studied. The ability of FeO-SM to neutralize the negative charge of DNA and protect it against DNaseΙ and ultrasonic waves was confirmed using an agarose gel electrophoresis assay.
Topics: Rosmarinus; Iron; Spermine; Antioxidants; Nanoparticles
PubMed: 36641537
DOI: 10.1038/s41598-023-27844-5 -
Biochimica Et Biophysica Acta Jan 2003Among polyamines (putrescine, spermidine, and spermine), spermine specifically induces cataract in an organ cultured lens. Spermine uptake nearly paralleled the cataract...
Among polyamines (putrescine, spermidine, and spermine), spermine specifically induces cataract in an organ cultured lens. Spermine uptake nearly paralleled the cataract formation. When polyamines were added to lens soluble proteins, spermine specifically induced turbidity. When lens soluble proteins were separated by gel chromatography, heavy-molecular-weight protein (HMW, high molecular form of alpha-crystallin) and proteins between betaH- and betaL-crystallin fractions reacted with spermine and aggregated. SDS-polyacrylamide gel electrophoresis of the aggregated proteins showed that 43-kDa lens protein was commonly observed in both aggregates. Spermine-affinity chromatography of the total soluble proteins showed the binding of HMW protein to the gel and the chromatogram of the second turbidity peak in the gel chromatography showed the binding of 43-kDa protein. These results indicated that 43-kDa protein, which is present as a subunit in HMW and also in free form, binds spermine and induces turbidity of lens soluble proteins and produces cataract in a cultured lens.
Topics: Animals; Cataract; Chromatography, Gel; Crystallins; Culture Techniques; Electrophoresis, Polyacrylamide Gel; Lens, Crystalline; Male; Rats; Rats, Wistar; Solubility; Spermine; Swine
PubMed: 12527409
DOI: 10.1016/s0925-4439(02)00215-6 -
Zhongguo Ying Yong Sheng Li Xue Za Zhi... May 2020To investigate the protective effect of spermine (Sp) on diabetic cardiomyopathy (DCM) and high glucose-induced cardiac fibroblasts (CFs), and to explore its mechanism....
To investigate the protective effect of spermine (Sp) on diabetic cardiomyopathy (DCM) and high glucose-induced cardiac fibroblasts (CFs), and to explore its mechanism. ①Animal experiments: 24 male Wistar rats were randomly divided into control group, type 1 diabetes group (TID) and spermine group (TID+Sp, each group n=8). TID rats were induced by streptozocin (STZ, 60 mg/kg), and TID+Sp rat were pretreated with spermine (Sp, 5 mg/(kg·d)) for 2 weeks before STZ injection. After 12 weeks of modeling, blood glucose, insulin levels, ejection fraction (EF) and shortening fraction (FS) were measured, and Masson staining and Sirius red staining were performed in the rat cardiac tissues. ②Cell experiments: primary CFs were extracted from newborn (1-3 d) Wistar rat hearts, and were randomly divided into control group, high-glucose group (HG) and HG+Sp group (n=6 per group). HG group was treated with 40 mmol/L glucose, and the HG+Sp group was pretreated with 5 μmol/L Sp for 30 min before HG treatment. The cell viability of CFs was detected by CCK8, the content of collagen in culture medium was analyzed by ELISA, and protein expressions of cell cycle related proteins (PCNA, CyclinD1 and P27) were detected by Western blot. Compared with control group, the blood glucose and collagen content were increased, and the insulin level and heart function were decreased in the T1D group. Meanwhile, HG induced an increasing of the cell viability, the collagen content in the medium and the expressions of PCNA and CyclinD1, while the expression of P27 was down-regulated. Spermine could reduce the above changes, manifested as improving the cardiac function, regulating the expression of cyclin and reducing the level of myocardial fibrosis. Spermine can alleviate myocardial fibrosis in diabetic cardiomyopathy, which mechanism is related to the regulation of cell cycle.
Topics: Animals; Blood Glucose; Cell Cycle; Cell Survival; Cells, Cultured; Diabetes Complications; Diabetic Cardiomyopathies; Fibroblasts; Fibrosis; Glucose; Heart; Male; Random Allocation; Rats; Rats, Wistar; Spermine
PubMed: 32981270
DOI: 10.12047/j.cjap.5952.2020.043 -
Neuroreport Jun 2015Polyamines (PAs), such as spermine and spermidine, modulate the activity of numerous receptors and channels in the central nervous system (CNS) and are stored in glial...
Polyamines (PAs), such as spermine and spermidine, modulate the activity of numerous receptors and channels in the central nervous system (CNS) and are stored in glial cells; however, little attention has been paid to their role in the regulation of connexin (Cx)-based gap junction channels. We have previously shown that PAs facilitate diffusion of Lucifer Yellow through astrocytic gap junctions in acute brain slices; therefore, we hypothesized that spermine can regulate Cx43-mediated (as the most abundant Cx in astrocytes) gap junctional communication. We used electrophysiological patch-clamp recording from paired Novikoff cells endogenously expressing Cx43 and HeLaCx43-EGFP transfectants to study pH-dependent modulation of cell-cell coupling in the presence or absence of PAs. Our results showed (i) a higher increase in gap junctional communication at higher concentrations of cytoplasmic spermine, and (ii) that spermine prevented uncoupling of gap junctions at low intracellular pH. Taken together, we conclude that spermine enhances Cx43-mediated gap junctional communication and may preserve neuronal excitability during ischemia and trauma when pH in the brain acidifies. We, therefore, suggest a new role of spermine in the regulation of a Cx43-based network under (patho)physiological conditions.
Topics: Cell Communication; Cell Line; Connexin 43; Electric Conductivity; Gap Junctions; HeLa Cells; Humans; Hydrogen-Ion Concentration; Spermine
PubMed: 26011388
DOI: 10.1097/WNR.0000000000000385 -
Journal of the American Dietetic... Jun 2007Reducing the concentration of polyamines (spermine, spermidine, and putrescine) in the body pool may slow the cancer process. Because dietary spermine, spermidine, and...
Reducing the concentration of polyamines (spermine, spermidine, and putrescine) in the body pool may slow the cancer process. Because dietary spermine, spermidine, and putrescine contribute to the body pool of polyamines, quantifying them in the diet is important. Limited information about polyamine content of food is available, especially for diets in the United States. This brief report describes the development of a polyamine database linked to the Fred Hutchinson Cancer Center food frequency questionnaire (FFQ). Values for spermine, spermidine, and putrescine were calculated and reported per serving size (nmol/serving). Of the foods from the database that were evaluated, fresh and frozen corn contain the highest levels of putrescine (560,000 nmol/serving and 902,880 nmol/serving) and spermidine (137,682 nmol/serving and 221,111 nmol/serving), and green pea soup contains the highest concentration of spermine (36,988 nmol/serving). The polyamine database and FFQ were tested with a convenience sample (n=165). Average daily polyamine intakes from the sample were: 159,133 nmol/day putrescine, 54,697 nmol/day spermidine, and 35,698 nmol/day spermine. Orange and grapefruit juices contributed the greatest amount of putrescine (44,441 nmol/day) to the diet. Green peas contributed the greatest amount of spermidine (3,283 nmol/day) and ground meat contributed the greatest amount of spermine (2,186 nmol/day). Development of this database linked to an FFQ provides a means of estimating polyamine intake and contributes to investigations relating polyamines to cancer.
Topics: Beverages; Databases, Factual; Food Analysis; Fruit; Humans; Meat; Neoplasms; Pisum sativum; Polyamines; Putrescine; Spermidine; Spermine; Zea mays
PubMed: 17524725
DOI: 10.1016/j.jada.2007.03.012