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1.
Mol Biol Rep ; 48(5): 4813-4835, 2021 May.
Article in English | MEDLINE | ID: mdl-34132942

ABSTRACT

Glioblastoma multiforme (GBM) is one of the aggressive brain cancers with patients having less survival period upto 12-15 months. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase, belongs to the phosphatidylinositol 3-kinases (PI3K) pathway and is involved in various cellular processes of cancer cells. Cancer metabolism is regulated by mTOR and its components. mTOR forms two complexes as mTORC1 and mTORC2. Studies have identified the key component of the mTORC2 complex, Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) plays a prominent role in the regulation of cancer cell proliferation and metabolism. Apart, growth factor receptor signaling such as epidermal growth factor signaling mediated by epidermal growth factor receptor (EGFR) regulates cancer-related processes. In EGFR signaling various other signaling cascades such as phosphatidyl-inositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR pathway) and Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) -dependent signaling cross-talk each other. From various studies about GBM, it is very well established that Rictor and EGFR mediated signaling pathways majorly playing a pivotal role in chemoresistance and tumor aggressiveness. Recent studies have shown that non-coding RNAs such as microRNAs (miRs) and long non-coding RNAs (lncRNAs) regulate the EGFR and Rictor and sensitize the cells towards chemotherapeutic agents. Thus, understanding of microRNA mediated regulation of EGFR and Rictor will help in cancer prevention and management as well as a future therapy.


Subject(s)
Carcinogenesis/metabolism , ErbB Receptors/metabolism , Glioblastoma , Rapamycin-Insensitive Companion of mTOR Protein/metabolism , TOR Serine-Threonine Kinases/metabolism , Brain Neoplasms/metabolism , Cell Proliferation , Cell Transformation, Neoplastic , Glioblastoma/diagnosis , Glioblastoma/metabolism , Humans , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , Signal Transduction
2.
Life Sci ; 277: 119504, 2021 Jul 15.
Article in English | MEDLINE | ID: mdl-33872660

ABSTRACT

The role of genetic and epigenetic factors in tumor initiation and progression is well documented. Histone deacetylases (HDACs), histone methyl transferases (HMTs), and DNA methyl transferases. (DNMTs) are the main proteins that are involved in regulating the chromatin conformation. Among these, histone deacetylases (HDAC) deacetylate the histone and induce gene repression thereby leading to cancer. In contrast, histone acetyl transferases (HATs) that include GCN5, p300/CBP, PCAF, Tip 60 acetylate the histones. HDAC inhibitors are potent drug molecules that can induce acetylation of histones at lysine residues and induce open chromatin conformation at tumor suppressor gene loci and thus resulting in tumor suppression. The key processes regulated by HDAC inhibitors include cell-cycle arrest, chemo-sensitization, apoptosis induction, upregulation of tumor suppressors. Even though FDA approved drugs are confined mainly to haematological malignancies, the research on HDAC inhibitors in glioblastoma multiforme and triple negative breast cancer (TNBC) are providing positive results. Thus, several combinations of HDAC inhibitors along with DNA methyl transferase inhibitors and histone methyl transferase inhibitors are in clinical trials. This review focuses on how HDAC inhibitors regulate the expression of coding and non-coding genes with specific emphasis on their anti-cancer potential.


Subject(s)
Histone Deacetylase Inhibitors/therapeutic use , Neoplasms/drug therapy , Neoplasms/genetics , Acetylation , Apoptosis/drug effects , Cell Cycle/drug effects , Chromatin/metabolism , Epigenesis, Genetic/drug effects , Epigenesis, Genetic/genetics , Epigenomics/methods , Gene Expression/drug effects , Histone Acetyltransferases/metabolism , Histone Deacetylase Inhibitors/metabolism , Histone Deacetylases/metabolism , Histones/metabolism , Humans , Neoplasms/metabolism , Protein Processing, Post-Translational/drug effects
4.
Environ Toxicol Pharmacol ; 79: 103415, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32470609

ABSTRACT

Catalase, an important antioxidant enzyme, is known to have a neuroprotective role against neurodegenerative disorder. Earlier study has focussed on benzothiazole-triazole hybrid molecules that are larger in size and molecular weight and inhibit the amyloid ß (Aß)-catalase interaction thus aid in neuroprotection. Here we have synthesized the novel benzothiazole molecules with low molecular weight using One-pot methodology and assayed the neuroprotective effects of the synthesized compounds in the U87 MG cell line under H2O2 induced stressed condition and compared with other cell lines such as breast cancer (MCF-7) and macrophage (RAW-264.7) using cell viability assay. These analogs were found to enhance the neuronal cell viability and protect neuronal cells from the ROS mediated neuronal damage induced by H2O2. Furthermore, compounds 6a, 6b, 6c, 6d, and 7a modulate catalase and enhanced the catalase activity up to 90 % during the H2O2 exposure in the U87MG cell line. These analogs (6a, 6b, 6c and 6d) have exhibited strong binding energies of -7.39, -7.52, -6.5 and -7.1 as observed by molecular modeling studies using AutoDockTool-1.5.6. Lig Plot + program using potent analogs 6b and 6c and catalase enzyme indicated the presence of hydrophobic interactions in the catalytic site of catalase enzyme. Furthermore, a simulation study was conducted between ligand and catalase protein by DESMOND software that further strengthens these ligand and enzyme interactions. In silico ADMET study was conducted by the Swiss ADME program revealed the drug-likeliness of these analogs. The present study has identified benzothiazole analogs such as 6b, 6c and 6d have potential catalase modulating activity and is comparable with that of known drug Valproic acid, thus help in neuroprotection. This study can be further taken up for the in vivo animal model study for the possible therapy.


Subject(s)
Antioxidants/pharmacology , Benzothiazoles/pharmacology , Neuroprotective Agents/pharmacology , Animals , Antioxidants/chemistry , Benzothiazoles/chemistry , Catalase/metabolism , Cell Line , Cell Survival/drug effects , Humans , Hydrogen Peroxide/toxicity , Mice , Molecular Docking Simulation , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/chemistry , Reactive Oxygen Species/metabolism
5.
Life Sci ; 164: 60-70, 2016 Nov 01.
Article in English | MEDLINE | ID: mdl-27596816

ABSTRACT

AIMS: miRNAs are small non-coding RNA molecules that regulate post-transcriptional gene expression. Here we have made an endeavor to search whether any miRNAs are involved in the regulation of BMI1 in breast cancer that leads to mitochondrial dependent apoptotic cell death. MAIN METHODS: Renilla luciferase reporter assay was performed to detect the ectopically expressed miRNAs that regulate the expression of 3' UTR of BMI1. MTT assay was performed to check the cytotoxicity level. Western blotting and qRT-PCR were performed to check the expression of BMI1, pro-apoptotic, anti-apoptotic proteins and mRNA expression levels respectively. JC-1 staining, Caspase-3, Caspase-6/9 assay and mitochondrial cytosolic fractionation were performed to monitor mitochondrial dependent apoptosis. Wound healing assay was performed to investigate migration. All experiments were performed upon miR-15a and miR-16 overexpression in MCF-7, MDAMB-231 breast cancer cells. KEY FINDINGS: In MCF-7, MDAMB-231 breast cancer cells luciferase reporter assay confirmed the significant reduction of reporter activity upon co-transfection of 3' UTR of BMI1 along with miR-15a and miR-16. miR-15a and miR-16 significantly down-regulated BMI1 protein and mRNA expression levels as well as anti-apoptotic protein BCL2 and up-regulated pro-apoptotic proteins. Ectopic expression of miR-15a, miR-16, increased mitochondrial ROS resulting in impaired mitochondrial membrane potential, followed by cytochrome-C release into the cytosol that activated Caspase-3 and Caspase-6/9 leading to intrinsic apoptosis. Additionally, it also inhibits migration. SIGNIFICANCE: Our results suggest that overexpression of miR-15a and miR-16 mediates down-regulation of BMI1, and leads to mitochondrial mediated apoptosis.


Subject(s)
Apoptosis/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , MicroRNAs/metabolism , Polycomb Repressive Complex 1/genetics , Blotting, Western , Breast Neoplasms/physiopathology , Cell Line, Tumor , Female , Humans , Polycomb Repressive Complex 1/metabolism , Polymerase Chain Reaction
6.
PLoS One ; 11(7): e0159092, 2016.
Article in English | MEDLINE | ID: mdl-27467502

ABSTRACT

Glioma amplified sequence 41(GAS41) is a potent transcription factor that play a crucial role in cell proliferation and survival. In glioblastoma, the expression of GAS41 at both transcriptional and post transcriptional level needs to be tightly maintained in response to cellular signals. Micro RNAs (miRNA) are small non coding RNA that act as important regulators for modulating the expression of various target genes. Studies have shown that several miRNAs play role in the post-transcriptional regulation of GAS41. Here we identified GAS41 as a novel target for endogenous miR-203 and demonstrate an inverse correlation of miR-203 expression with GAS41 in glioma cell lines (HNGC2 and U87). Over expression of miR-203 negatively regulates GAS41 expression in U87 and HNGC2 cell lines. Moreover, miR-203 restrained miR-10b action by suppressing GAS41. GAS41 is essential for repressing p53 in tumor suppressor pathway during cell proliferation. Enforced expression of GAS41 produced contradictory effect on miR-203 but was able to enhance p53 tumor suppressor pathway associated protein. It was also found that miR-203 maintains the stability of p53 as knock down of p53 expression using siRNA resulted in down regulation of pri-miR and mature miR-203 expression. Conversely reconstitution of miR-203 expression induced apoptosis and inhibited migratory property of glioma cells. Taken together, we show that miR-203 is a key negative regulator of GAS41 and acts as tumor suppressor microRNA in glioma.


Subject(s)
Brain Neoplasms/pathology , Cell Proliferation/genetics , Glioblastoma/pathology , MicroRNAs/genetics , Neoplasm Metastasis/genetics , Transcription Factors/genetics , Apoptosis , Brain Neoplasms/genetics , Cell Line, Tumor , Down-Regulation , Gene Expression Regulation, Neoplastic , Glioblastoma/genetics , Humans , Proto-Oncogene Proteins p21(ras)/genetics , Transcription, Genetic , Tumor Suppressor Protein p53/metabolism
7.
Bioorg Med Chem Lett ; 26(8): 2077-83, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26948540

ABSTRACT

A series of anilinonicotinyl linked pyrazolo[1,5-a]pyrimidine conjugates (6a-x) were synthesized and evaluated for their antiproliferative activity. Some of these conjugates exhibited promising cytotoxic effects in the MCF-7 cell line and among these 6a and 6c exhibited significant effects, apart from G2/M cell cycle arrest. Interestingly they showed profound effects on cyclin D1, Bcl-2 and survivin proteins that regulate breast cancer cell proliferation. Moreover, ER alpha protein expression was studied to understand regulatory role of these conjugates on estrogen activity in estrogen positive breast cancer cells like MCF-7 and compounds 6a and 6c reduced their activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Estrogens/metabolism , Nicotine/analogs & derivatives , Pyrimidines/pharmacology , Signal Transduction/drug effects , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Molecular Structure , Nicotine/chemical synthesis , Nicotine/chemistry , Nicotine/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
8.
Life Sci ; 151: 264-276, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26979778

ABSTRACT

AIMS: Breast cancer is highly resistant to chemotherapeutic approach and hence, alternative strategies have been developed to fight against this heterogeneous group of disease. In particular, many studies have demonstrated about various drugs for the treatment of breast cancer. In our study, we assessed the anti-angiogenenic activities of Bisindole-PBD (5b) in MCF-7 and MDA-MB-231 cell lines. MAIN METHODS: In vitro Endothelial Cell (HUVEC) Tube Formation Assay was performed to show inhibitory role of 5b along with its role upon wound healing process in breast cancer cells in vitro. Semi-quantitative reverse transcription PCR (RT-PCR) was also done to examine the expression of VEGF in response to 5b in breast cancer cells and in HUVEC cells. siRNA transfection study explored STAT3 mediated VEGF transcription in breast cancer cells MCF-7 and MDA-MB-231. CAM assay was performed to see the role of 5b on vessel formation in chicken embryo. KEY FINDINGS: From in vitro data we have demonstrated that 5b played a role in regulation of breast cancer cell proliferation by inhibiting angiogenesis. Test drug 5b suppressed the expression VEGF at both transcriptional and post transcriptional levels. Apart from this, there was significant down regulation in STAT3 level after drug treatment, which was found to be involved in the VEGF transcription. Metastasis related MMP-2 and MMP-9 expressions were also modulated by 5b. In vivo study by Chick Chorioallantoic Membrane (CAM) Assay also showed anti-angiogenesis role of the test drug which was consistent with the in vitro data. SIGNIFICANCE: Altogether, our data demonstrated 5b as potent small molecule with anti-angiogenic activities.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Dioxins/pharmacology , Indoles/pharmacology , Neovascularization, Pathologic/metabolism , STAT3 Transcription Factor/metabolism , Vascular Endothelial Growth Factor A/biosynthesis , Animals , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Chick Embryo , Down-Regulation/drug effects , Female , Humans , Matrix Metalloproteinase 2/biosynthesis , Matrix Metalloproteinase 9/biosynthesis , Neovascularization, Pathologic/drug therapy , Wound Healing/drug effects
9.
Apoptosis ; 21(3): 269-82, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26711898

ABSTRACT

Histone modulations have been implicated in various cellular and developmental processes where in Drosophila Mof is involved in acetylation of H4K16. Reduction in the size of larval imaginal discs is observed in the null mutants of mof with increased apoptosis. Deficiency involving Hid, Reaper and Grim [H99] alleviated mof (RNAi) induced apoptosis in the eye discs. mof (RNAi) induced apoptosis leads to activation of caspases which is suppressed by over expression of caspase inhibitors like P35 and Diap1 clearly depicting the role of caspases in programmed cell death. Also apoptosis induced by knockdown of mof is rescued by JNK mutants of bsk and tak1 indicating the role of JNK in mof (RNAi) induced apoptosis. The adult eye ablation phenotype produced by ectopic expression of Hid, Rpr and Grim, was restored by over expression of Mof. Accumulation of Mof at the Diap1 promoter 800 bp upstream of the transcription start site in wild type larvae is significantly higher (up to twofolds) compared to mof (1) mutants. This enrichment coincides with modification of histone H4K16Ac indicating an induction of direct transcriptional up regulation of Diap1 by Mof. Based on these results we propose that apoptosis triggered by mof (RNAi) proceeds through a caspase-dependent and JNK mediated pathway.


Subject(s)
Apoptosis/genetics , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Eye/growth & development , Gene Expression Regulation, Developmental , Histone Acetyltransferases/metabolism , Imaginal Discs/abnormalities , Inhibitor of Apoptosis Proteins/genetics , MAP Kinase Signaling System/physiology , Nuclear Proteins/metabolism , Acetylation , Animals , Caspases/metabolism , Drosophila melanogaster/cytology , Drosophila melanogaster/genetics , Gene Knockdown Techniques , Histone Acetyltransferases/genetics , Histones/metabolism , Imaginal Discs/cytology , Larva , MAP Kinase Kinase Kinases/genetics , MAP Kinase Kinase Kinases/metabolism , Male , Neuropeptides/genetics , Neuropeptides/metabolism , Nuclear Proteins/genetics , Phenotype , Promoter Regions, Genetic , RNA Interference , Transcription, Genetic , Up-Regulation
10.
PLoS One ; 10(11): e0142006, 2015.
Article in English | MEDLINE | ID: mdl-26551008

ABSTRACT

Tumor microenvironment play role in angiogenesis and carcinogenesis. Etoposide, a known topoisomerase II inhibitor induces DNA damage resulting in cell cycle arrest. We developed a novel Etoposide analogue, Quinazolino-4ß-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis. We evaluated its role on expression of microRNAs-15, 16, 17 and 221 and its targets Bcl-2, STAT3 and VEGF that dictate cell proliferation and angiogenesis. Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3. We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.


Subject(s)
Breast Neoplasms/drug therapy , Cell Proliferation/drug effects , Etoposide/analogs & derivatives , MicroRNAs/biosynthesis , Podophyllotoxin/analogs & derivatives , Quinazolines/pharmacology , STAT3 Transcription Factor/metabolism , Apoptosis/drug effects , Breast Neoplasms/pathology , Caspase 9/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Survival/drug effects , DNA Damage/drug effects , Enzyme Activation/drug effects , Etoposide/pharmacology , Gene Expression Regulation, Neoplastic , Human Umbilical Vein Endothelial Cells/drug effects , Humans , MCF-7 Cells , MicroRNAs/genetics , Models, Molecular , Molecular Docking Simulation , Neovascularization, Pathologic/pathology , Podophyllotoxin/pharmacology , Protein Binding , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA Interference , RNA, Small Interfering/genetics , Vascular Endothelial Growth Factor A/metabolism
11.
Cancer Biol Ther ; 16(10): 1486-501, 2015.
Article in English | MEDLINE | ID: mdl-26192233

ABSTRACT

In a previous study we reported the role of potent bisindole-PBD conjugate as an inclusion in the arsenal of breast cancer therapeutics. In breast cancer cell proliferation, PI3K/AKT/mTOR pathway plays a crucial role by prosurvival mechanism that inhibits programmed cell death. Here, 2 breast cancer cells lines, MCF-7 and MDA-MB-231 were treated with Vorinostat (suberoylanilide hydroxamic acid / SAHA) and bisindole-PBD (5b). We have investigated the effect on PI3K/AKT/mTOR pathway and SIRT expression including epigenetic regulation. There was consistent decrease in the level of PI3K, AKT, mTOR proteins upon treatment of 5b in both MCF-7 and MDA-MB-231 cell lines compared to untreated controls. Treatment with caspase inhibitor (Q-VD-OPH) confirmed that the effect of 5b on PI3K signaling was ahead of apoptosis. Real time PCR and western blot analysis showed profound reduction in the mRNA and protein levels of SIRT1 and SIRT2. Molecular docking studies also supported the interaction of 5b with various amino acids of SIRT2 proteins. Treatment with 5b caused epigenetic changes that include increase of acetylated forms of p53, increase of histone acetylation at p21 promoter as well as decrease in methylation state of p21 gene. Compound 5b thus acts as SIRT inhibitor and cause p53 activation via inhibition of growth factor signaling and activation of p53 dependent apoptotic signaling. This present study focuses bisindole-PBD on epigenetic alteration putting 5b as a promising therapeutic tool in the realm of breast cancer research.


Subject(s)
Breast Neoplasms/genetics , Sirtuin 1/genetics , Sirtuin 1/metabolism , Tumor Suppressor Protein p53/metabolism , Breast Neoplasms/metabolism , Cell Proliferation , Female , Humans
12.
Eur J Med Chem ; 94: 87-101, 2015 Apr 13.
Article in English | MEDLINE | ID: mdl-25757092

ABSTRACT

A series of novel quinazolinone hybrids were synthesized by employing click chemistry and evaluated for anti-proliferative activities against MCF-7, HeLa and K562 cell lines. Among these cell lines, HeLa cells were found to respond effectively to these quinazolinone hybrids with IC50 values ranging from 5.94 to 16.45 µM. Some of the hybrids (4q, 4r, 4e, 4k, 4t, 4w) with promising anti-cancer activity were further investigated for their effects on the cell cycle distribution. FACS analysis revealed the G1 cell cycle arrest nature of these hybrids. Further to assess the senescence inducing ability of these compounds, a senescence associated ß-gal assay was performed. The senescence inducing nature of these compounds was supported by the effect of hybrid (4q) on p16 promoter activity, the marker for senescence. Moreover, cells treated with most effective compound (4q) show up-regulation of p53, p21 and down-regulation of HDAC-1, HDAC-2, HDAC-5 and EZH2 mRNA levels. Docking results suggest that, the triazole nitrogen showed Zn(+2) mediated interactions with the histidine residue of HDACs.


Subject(s)
Apoptosis/drug effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Pyrroles/chemistry , Quinazolinones/pharmacology , Quinones/chemistry , Cell Cycle/drug effects , Cellular Senescence/drug effects , Click Chemistry , Enhancer of Zeste Homolog 2 Protein , HeLa Cells/drug effects , HeLa Cells/metabolism , Histone Deacetylase 1/chemistry , Histone Deacetylase 1/metabolism , Histone Deacetylase 2/chemistry , Histone Deacetylase 2/metabolism , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/chemistry , Histone Deacetylases/genetics , Humans , Inhibitory Concentration 50 , K562 Cells/drug effects , MCF-7 Cells/drug effects , Molecular Docking Simulation , Polycomb Repressive Complex 2/chemistry , Polycomb Repressive Complex 2/metabolism , Quinazolinones/chemical synthesis , Quinazolinones/chemistry , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Proteins/metabolism
13.
Mol Biol Rep ; 42(7): 1211-24, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25648260

ABSTRACT

Putatively functional polymorphisms of one-carbon and xenobiotic metabolic pathways influence susceptibility for wide spectrum of diseases. The current study was aimed to explore gene-gene interactions among these two metabolic pathways in four diseases i.e. breast cancer, systemic lupus erythematosus (SLE), coronary artery disease (CAD) and Parkinson's disease (PD). Multifactor dimensionality reduction analysis was carried out on four case-control datasets. Cross-talk was observed between one-carbon and xenobiotic pathways in breast cancer (RFC 80 G>A, COMT H108L and TYMS 5'-UTR 28 bp tandem repeat) and SLE (CYP1A1 m1, MTRR 66 A>G and GSTT1). Gene-gene interactions within one-carbon metabolic pathway were observed in CAD (GCPII 1561 C>T, SHMT 1420 C>T and MTHFR 677 C>T) and PD (cSHMT 1420 C>T, MTRR 66 A>G and RFC1 80 G>A). These interaction models showed good predictability of risk for PD (The area under the receiver operating characteristic curve (C) = 0.83) and SLE (C = 0.73); and moderate predictability of risk for breast cancer (C = 0.64) and CAD (C = 0.63). Cross-talk between one-carbon and xenobiotic pathways was observed in diseases with female preponderance. Gene-gene interactions within one-carbon metabolic pathway were observed in diseases with male preponderance.


Subject(s)
Breast Neoplasms/genetics , Coronary Artery Disease/genetics , Lupus Erythematosus, Systemic/genetics , Multifactor Dimensionality Reduction , Oxidoreductases/genetics , Parkinson Disease/genetics , Transferases/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carbon/metabolism , Case-Control Studies , Coronary Artery Disease/metabolism , Coronary Artery Disease/pathology , Datasets as Topic , Epistasis, Genetic , Factor Analysis, Statistical , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/pathology , Male , Metabolic Networks and Pathways/genetics , Oxidoreductases/metabolism , Parkinson Disease/metabolism , Parkinson Disease/pathology , Polymorphism, Single Nucleotide , Sex Factors , Transferases/metabolism , Xenobiotics/metabolism
14.
Carbohydr Polym ; 120: 102-14, 2015 Apr 20.
Article in English | MEDLINE | ID: mdl-25662693

ABSTRACT

Levan is a homopolymer of fructose naturally obtained from both plants and microorganisms. Microbial levans are more advantageous, economical and industrially feasible with numerous applications. Bacterial levans are much larger than those produced by plants with multiple branches and molecular weights ranging from 2 to 100 million Da. However levans from plants generally have molecular weights ranging from about 2000 to 33,000 Da. Microbial levans have wide range of applications in food, medicine, pharmaceutical, cosmetic and commercial industrial sectors. With excellent polymeric medicinal properties and ease of production, microbial levan appear as a valuable and versatile biopolymer of the future. The present article summarizes and discusses the most essential properties of bioactive microbial levan and recent developments in its production, characterization and the emerging applications in health and industry.


Subject(s)
Bacteria/chemistry , Fructans/analysis , Fructans/biosynthesis , Fructans/economics , Molecular Weight , Plants/chemistry
15.
Bioorg Med Chem Lett ; 25(3): 654-8, 2015 Feb 01.
Article in English | MEDLINE | ID: mdl-25563891

ABSTRACT

A series of novel triazole linked N-(pyrimidin-2yl)benzo[d]thiazol-2-amine 5a-k were synthesized and evaluated for anticancer activity against breast (MCF-7), lung (A549) and skin (A375) cancer cell lines and their cytotoxic effects were compared against normal breast epithelial cells. The effect of compounds on cell cycle of MCF-7 breast cancer cell line was investigated by FACS. Result indicated G2/M cell cycle arrest of MCF-7 cells. Further promising compounds 5b, 5g, 5h and 5i were tested for their apoptosis inducing ability as well as inhibitory activity against key proteins NF-kB, Survivin, CYP1A1, and ERK1/2 which help in cancer cell survival and proliferation. The apoptotic aspect of these compounds is further evidenced by increase in the activity of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in highly malignant breast cancers and can be selected for further biological studies.


Subject(s)
Antineoplastic Agents/chemical synthesis , Thiazoles/chemistry , Triazoles/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Caspase 9/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cytochrome P-450 CYP1A1/antagonists & inhibitors , Cytochrome P-450 CYP1A1/metabolism , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , M Phase Cell Cycle Checkpoints/drug effects , MCF-7 Cells , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Pyrimidines/chemistry , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/toxicity
16.
Cancer Biol Ther ; 15(10): 1320-32, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25010292

ABSTRACT

DNA damage response (DDR) that includes cell cycle check points, DNA repair, apoptosis, and senescence is intimately linked with cancer. It shields an organism against cancer development when genomic integrity fails. DNA repair pathways protect the cells from tumor progression caused as a result of DNA damage induced by irradiation or due to chemotherapeutic treatment. Many promising anticancer agents have been identified that target specific DNA repair pathways in response to DNA damage thereby leading to apoptosis. Here we identified a novel bisindole-PBD conjugate that possess potent anticancer activity in breast cancer cells. Further studies aimed at understanding the mechanism of action of the molecule showed its role in DNA damage induced apoptosis via inhibition of DNA repair pathway. Trypan blue and BrdU assay exhibited a dose-dependent effect. Single-stranded DNA damage was observed by COMET assay. In addition DNA damage induced ROS generation with simultaneous activation of ATM and ATR upon compound treatment was observed. Further downregulation of Bcl-XL and activation of Bax showed DNA damage induced apoptosis in MCF-7 and MDAMB-231 cells. In conclusion, it can be summarized that bisindole-PBD conjugate induces DNA damage in a dose dependent (2, 4, and 8 µM) manner by inhibiting the DNA repair genes.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzodiazepines/pharmacology , DNA Damage/drug effects , DNA Repair/drug effects , Indoles/pharmacology , Pyrroles/pharmacology , Antineoplastic Agents/chemistry , Benzodiazepines/chemistry , Cell Line, Tumor , Humans , Indoles/chemistry , Mitochondrial Membranes/drug effects , Pyrroles/chemistry , Reactive Oxygen Species/metabolism , bcl-2-Associated X Protein/metabolism , bcl-X Protein/metabolism
17.
Bioorg Med Chem Lett ; 24(5): 1389-96, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24508135

ABSTRACT

Rugulactone and its analogues were synthesized following Horners-Wadsworth-Emmons and ring-closing metathesis as the key reactions. A library of new rugulactone analogues were designed, synthesized and evaluated for their anticancer activity in breast cancer cells. All analogues have shown anti-proliferative activity, while some of them exhibited significant cytotoxicity. In assays related to cell-cycle distribution, these conjugates induced G1 cell-cycle arrest in MDA-MB-231 cells. The cell cycle arrest nature was further confirmed by examining the effect on Cyclin E and Cdk2 proteins that acts at G1-S phase transition. Immunocytochemistry assay revealed that these compounds inhibited nuclear translocation of NF-κB protein, thereby activation of NF-κB was inhibited. The expression of NF-κB target genes such as Cyclin D1 and Bcl-xL were severely affected. Apart from acting on NF-κB, these compounds also regulate class I Histone deacetylase proteins such as (HDAC-3 and 8) that have a crucial and regulatory role in cell-proliferation. Simultaneously, the apoptotic inducing nature of these compounds was confirmed by activation of PARP protein, a protein that plays a key role in DNA damage and repair pathways. Among all compounds of this series 3g is the most potent compound and can be used for further studies.


Subject(s)
Antineoplastic Agents/chemistry , Lactones/chemistry , NF-kappa B/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cyclin E/metabolism , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase Inhibitor p27/genetics , Cyclin-Dependent Kinase Inhibitor p27/metabolism , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Lactones/chemical synthesis , Lactones/pharmacology , MCF-7 Cells , NF-kappa B/metabolism , Oncogene Proteins/metabolism , Poly(ADP-ribose) Polymerases/metabolism , Structure-Activity Relationship , Transcription, Genetic/drug effects , bcl-X Protein/metabolism
18.
FASEB J ; 28(2): 655-66, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24165481

ABSTRACT

The role of Ago-1 in microRNA (miRNA) biogenesis has been thoroughly studied, but little is known about its involvement in mitotic cell cycle progression. In this study, we established evidence of the regulatory role of Ago-1 in cell cycle control in association with the G2/M cyclin, cyclin B. Immunostaining of early embryos revealed that the maternal effect gene Ago-1 is essential for proper chromosome segregation, mitotic cell division, and spindle fiber assembly during early embryonic development. Ago-1 mutation resulted in the up-regulation of cyclin B-Cdk1 activity and down-regulation of p53, grp, mei-41, and wee1. The increased expression of cyclin B in Ago-1 mutants caused less stable microtubules and probably does not produce enough force to push the nuclei to the cortex, resulting in a decreased number of pole cells. The role of cyclin B in mitotic defects was further confirmed by suppressing the defects in the presence of one mutant copy of cyclin B. We identified involvement of 2 novel embryonic miRNAs--miR-981 and miR--317-for spatiotemporal regulation of cyclin B. In summary, our results demonstrate that the haploinsufficiency of maternal Ago-1 disrupts mitotic chromosome segregation and spindle fiber assembly via miRNA-guided control during early embryogenesis in Drosophila. The increased expression of cyclin B-Cdk1 and decreased activity of the Cdk1 inhibitor and cell cycle checkpoint proteins (mei-41 and grp) in Ago-1 mutant embryos allow the nuclei to enter into mitosis prematurely, even before completion of DNA replication. Thus, our results have established a novel role of Ago-1 as a regulator of the cell cycle.


Subject(s)
Argonaute Proteins/metabolism , Cyclin B/metabolism , Drosophila Proteins/metabolism , Embryonic Development/physiology , Mitosis/physiology , Animals , Argonaute Proteins/genetics , Cell Line , Checkpoint Kinase 1 , Cyclin B/genetics , Drosophila , Drosophila Proteins/genetics , Embryonic Development/genetics , Immunohistochemistry , MicroRNAs/genetics , Mitosis/genetics , Real-Time Polymerase Chain Reaction
19.
Bioorg Med Chem ; 21(21): 6414-26, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-24055291

ABSTRACT

A series of new conjugates of quinazolino linked 4ß-amidopodophyllotoxins 10aa-af and 10ba-bf were synthesized and evaluated for their anticancer activity against human pancreatic carcinoma (Panc-1) as well as breast cancer cell lines such as MCF-7 and MDA-MB-231 by employing MTT assay. Among these conjugates, some of them like 10bc, 10bd, 10be and 10bf exhibited high potency of cytotoxicity. Flow cytometric analysis showed that these conjugates arrested the cell cycle in the G2/M phase and caused the increase in expression of p53 and cyclin B1 protein with concomitant decrease in Cdk1 thereby suggesting the inhibitory action of these conjugates on mitosis. Interestingly, we observed a decrease in expression of proteins that control the tumor micro environment such as VEGF-A, STAT-3, ERK1/2, ERK-p, AKT-1 ser 473 phosphorylation in compounds treated breast cancer cells. Further, these effective conjugates have exhibited inhibitory action on integrin (αVßIII). Furthermore, the MCF-7 cells that were arrested and lost the proliferative capacity undergo mitochondrial mediated apoptosis by activation of caspases-9. Thus these conjugates have the potential to control breast cancer cell growth by effecting tumor angiogenesis and invasion.


Subject(s)
Antineoplastic Agents/chemistry , Podophyllotoxin/chemistry , Quinazolinones/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Female , G2 Phase Cell Cycle Checkpoints/drug effects , Human Umbilical Vein Endothelial Cells , Humans , M Phase Cell Cycle Checkpoints/drug effects , MCF-7 Cells , Membrane Potential, Mitochondrial/drug effects , Neovascularization, Physiologic/drug effects , Signal Transduction/drug effects
20.
Bioorg Med Chem Lett ; 23(20): 5699-706, 2013 Oct 15.
Article in English | MEDLINE | ID: mdl-23992861

ABSTRACT

It has previously been shown that anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates activate p53 and cause apoptosis in cervical cancer cells such as HeLa and SiHa. Here we establish the role of these conjugates in activating p53 pathway by phosphorylation at Ser15, 20 and 46 residues and downregulate key oncogenic proteins such as MYCN and Mdm2 in IMR-32 neuroblastoma cells. Compounds decreased the proliferation rate of neuroblastoma cells such as IMR-32, Neuro-2a, SK-N-SH. Compound treatment resulted in G2/M cell cycle arrest. The expression of p53 dependent genes such as p21, Bax, caspases was increased with concomitant decrease of the survival proteins as well as anti-apoptotic proteins such as Akt1, E2F1 and Bcl2. In addition the expression of important microRNAs such as miR-34a, c, miR-200b, miR-107, miR-542-5p and miR-605 were significantly increased that eventually lead to the activation of apoptotic pathway. Our data revealed that conjugates of this nature cause cell cycle arrest and apoptosis in IMR-32 cells [MYCN (+) with intact wild-type p53] by activating p53 signalling and provides a lead for the development of anti-cancer therapeutics.


Subject(s)
Antineoplastic Agents/chemistry , MicroRNAs/metabolism , Pyrazoles/chemistry , Pyrimidines/chemistry , ortho-Aminobenzoates/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , G2 Phase Cell Cycle Checkpoints/drug effects , Gene Expression Regulation, Neoplastic , HeLa Cells , Humans , M Phase Cell Cycle Checkpoints/drug effects , N-Myc Proto-Oncogene Protein , Neuroblastoma/metabolism , Neuroblastoma/pathology , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Oncogene Proteins/antagonists & inhibitors , Oncogene Proteins/genetics , Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Purines/chemistry , Purines/toxicity , Roscovitine , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
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