Publications by authors named "Suresh Kumar Muthuvel"

10 Publications

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Polymorphisms of T- cell leukemia 1A gene loci are not related to the development of adjuvant letrozole-induced adverse events in breast cancer.

PLoS One 2021 24;16(3):e0247989. Epub 2021 Mar 24.

Department of Pharmacology, Centre for Advanced Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.

Letrozole, an aromatase inhibitor (AI), is the first-line adjuvant drug for treating hormone receptor-positive (HR+) breast cancer in postmenopausal women. However, harmful adverse events (AEs) and significant differences in drug response among individuals remain a significant problem in clinical application. Current evidence suggests that the observed individual variation in the treatment outcomes of AI is conferred by genetic variants. Hence, in this study, we examined the association of TCL1A gene polymorphisms with letrozole-induced AEs. The study subjects were postmenopausal HR+ breast cancer patients who were receiving adjuvant letrozole. Genomic DNA was isolated by a routine standard phenol-chloroform method. In total, 198 South Indian patients were genotyped for four single nucleotide polymorphisms (SNPs) in the TCL1A gene loci by the TaqMan allelic discrimination assay using the RT-PCR system. We used the odds ratio and 95% confidence interval to assess the genetic association. Musculoskeletal (MS) AEs and vasomotor symptoms (VMSs) are the most common side effects observed in the study cohort. Among 198 patients, 81 experienced musculoskeletal toxicity, reporting MS-AEs, 57 had VMSs, and 33 of them had both. The most frequently identified polymorphic variants in the patient series were rs11849538 (G), with an allele frequency of about 27.3%, followed by rs7158782-G (27.3%), rs7159713-G (25.8%), and rs2369049-G (22.5%). The genetic association analysis indicated no significant difference in the proportion of TCL1A gene variants between patients with and without AEs on either MS-AEs or VMSs. Though we observed high LD in all patient groups, the inferred haplotypes displayed a non-significant association with letrozole-induced specific AEs. However, the SNP functionality analysis by RegulomeDB provided a 2b rank score for rs7158782, suggesting a potential biological function. Our findings suggest that TCL1A gene polymorphisms may not play any role in the prediction of letrozole-induced AEs in South Indian HR+ breast cancer patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247989PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990231PMC
March 2021

Association of CYP19A1 gene variations with adjuvant letrozole-induced adverse events in South Indian postmenopausal breast cancer cohort expressing hormone-receptor positivity.

Breast Cancer Res Treat 2020 Jul 8;182(1):147-158. Epub 2020 May 8.

Department of Pharmacology, Centre for Advanced Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.

Purpose: Musculoskeletal adverse events (MS-AEs) and vasomotor symptoms (VMSs) are the major side-effects of newer generation non-steroidal aromatase inhibitor (AI), letrozole. Single-nucleotide polymorphisms (SNPs) in CYP19A1 gene coding for the enzyme aromatase are related to AI treatment-associated adverse drug reactions. Therefore, we aimed to determine whether SNPs in the CYP19A1 gene are associated with adjuvant letrozole-induced 'specific' AEs in postmenopausal hormone receptor-positive (HR+) breast cancer patients.

Methods: Genomic DNA was isolated from 198 HR+ breast cancer patients by the phenol-chloroform method, and eleven SNPs in the CYP19A1 gene were genotyped by TaqMan genotyping assays on the qRT-PCR system. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, and the data were analyzed using SPSS v19.0 and Haploview v4.2 statistical software.

Results: Subjects carrying the genetic variants of CYP19A1 gene SNP rs700519 had significantly higher odds (OR 2.33; 95% CI [1.29-4.20], P = 0.0057) of MS-AEs under dominant statistical effect. The frequency of the two distinct haplotypes that include the variant allele 'T' at rs700519 locus, H5-GCTATCTGGCG (P = 0.042) and H11-GCTATTGCACG (P = 0.013) were significantly higher in patients with musculoskeletal toxicity than in those without MS-AEs and thus predisposing to MS-AEs. Similarly, H6-GCCAGCTGGCG (P = 0.037) haplotype exhibited higher frequencies in patients presented with VMSs. However, no such association was observed between CYP19A1 genotypes and VMSs.

Conclusions: To the best of our knowledge, this is the first study assessing the impact of CYP19A1 genetic variations with adjuvant letrozole treatment-associated AEs in Indian women. Genetic variations in the CYP19A1 gene is associated with letrozole-induced AEs and warrants further investigation in larger cohorts to validate this finding.
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http://dx.doi.org/10.1007/s10549-020-05656-9DOI Listing
July 2020

Unveiling anticancer potential of glibenclamide: Its synergistic cytotoxicity with doxorubicin on cancer cells.

J Pharm Biomed Anal 2018 May 14;154:294-301. Epub 2018 Mar 14.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India. Electronic address:

Drug repurposing has been an emerging therapeutic strategy, which involves exploration of a new therapeutic approach for the use of an existing drug. Glibenclamide (Gli) is an anti-diabetic sulfonylurea drug extensively used for the treatment of type-2 diabetes, it has also been shown to possess anti-proliferative effect against several types of tumors. The present study was executed to understand the mechanisms underlying the interaction of Gli with DNA under physiological conditions. The binding mechanism of Gli with DNA was scrutinized by UV-vis absorption spectroscopy and fluorescence emission spectroscopy. The conformational changes and electrochemical properties were analyzed by circular dichroism spectroscopy and cyclic voltammetry. Isothermal titration calorimetry was employed to examine the thermodynamic changes and molecular docking technique used to analyze the interaction mode of Gli with DNA. The spectroscopic studies revealed that Gli interacts with DNA through groove binding mode. Further, isothermal titration calorimetry depicted a stronger mode of interaction favorably groove-binding. Recently, systemic combination therapy has shown significant promise in inhibiting multiple targets simultaneously yielding high therapeutic competence with lesser side effects. With this concern, we intended to study the combined cytotoxicity of Gli with doxorubicin (Dox). The results of MTT assay and acridine orange (AO)/ethidium bromide (EtBr) staining showed synergistic cytotoxicity of Gli + Dox combination on HepG2 & A549 cells. The present study documents the intricate mechanism of Gli-DNA interaction and delivers a multifaceted access for chemotherapy by Gli + Dox combination.
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http://dx.doi.org/10.1016/j.jpba.2018.03.025DOI Listing
May 2018

Molecular docking and dynamics studies of 4-anilino quinazolines for epidermal growth factor receptor tyrosine kinase to find potent inhibitor.

J Recept Signal Transduct Res 2018 Oct - Dec;38(5-6):475-483

b Department of Pharmaceutical Chemistry , Mother Theresa Post Graduate and Research Institute of Health Sciences , Gorimedu , Pondicherry , India.

A series of novel 4-anilino quinazoline derivatives were taken based on the literature study and optimized with Autodock version 4.2 and molecular dynamics (MD) protocol to investigate the interaction between the target compounds and the amino acid residues of target protein epidermal growth factor receptor (EGFR) tyrosine kinase (PDB ID: 1M17). The free energies of binding and inhibition constants (Ki) of the docked ligands were calculated by the Lamarckian genetic algorithm (LGA). The docking results showed that the compounds SGQ4, DMUQ5, 6AUQ6, and PTQ8 had produced significant docking affinity for the protein tyrosine kinase with the binding energy of -7.46, -7.31, -6.85, and -6.74 kcal/mol, respectively, compared to the standard inhibitor Erlotinib (binding energy: -3.84 kcal/mol). Furthermore, molecular dynamics simulations (MDS) were performed using Gromacs to investigate the stability of a ligand-protein complex. The combined analysis of root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of 1M17 protein with docked ligands reveals that 1M17 protein has more stability when it interacts reacts with the inhibitor. Molecular descriptive properties and toxicity profile predicted by software. All the designed molecules passed Lipinski's rule of five successfully and they were found to be safe.
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http://dx.doi.org/10.1080/10799893.2019.1590411DOI Listing
September 2019

Anticancer potential of ZnO nanoparticle-ferulic acid conjugate on Huh-7 and HepG2 cells and diethyl nitrosamine induced hepatocellular cancer on Wistar albino rat.

Nanomedicine 2018 02 21;14(2):415-428. Epub 2017 Nov 21.

Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India. Electronic address:

Drawbacks and limitations of recently available therapies to hepatocellular cancer (HCC) devoted the scientist to focus on emerging new strategies. ZnO nanoparticles (ZnONPs) based chemotherapeutics has been emanating as a promising approach to maximize therapeutic synergy facilitating the discovery of novel multitargeted combinations. In the present study we conjugated ZnONPs with ferulic acid (ZnONPs-FAC) characterized by computational, spectroscopic and microscopic techniques. In vitro anticancer potential has been evaluated by assessing cell viability, morphology, ROS generation, mitochondrial membrane permeability, comet assay, immunofluorescent staining of 8-OHdG, Ki67 and γ-H2AX, cell cycle analysis and western blot analysis and in vivo anticancer potential against DEN induced HCC was analyzed by histopathological and immunohistochemical methods. The results revealed that ZnONPs-FAC induces cell death through apoptosis and can suppress the DEN-induced HCC. Our study documents therapeutic potential of nanoparticle conjugated with phytochemicals, suggesting a new platform for combinatorial chemotherapy.
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http://dx.doi.org/10.1016/j.nano.2017.11.003DOI Listing
February 2018

Cloning, expression of b-1,3-1,4 glucanase from Bacillus subtilis SU40 and the effect of calcium ion on the stability of recombinant enzyme: in vitro and in silico analysis.

Bioinformation 2013 6;9(19):958-62. Epub 2013 Dec 6.

Department of Biotechnology, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India.

A new glucanolytic bacterial strain, SU40 was isolated, and identified as Bacillus subtilis on the basis of 16S rRNA sequence homology and phylogenetic tree analysis. The gene encoding β-1,3-1,4-glucanase was delineated, cloned into pET 28a+ vector and heterologously overexpressed in Escherichia coli BL21(DE3). The purified recombinant enzyme was about 24 kDa. The enzyme exhibited maximum activity (36.84 U/ml) at 60°C, pH 8.0 and maintained 54% activity at 80°C after incubation for 60 min. The enzyme showed activity against β-glucan, lichenan, and xylan. Amino acid sequence shared a conserved motif EIDIEF. The predicted three-dimensional homology model of the enzyme showed the presence of catalytic residues Glu105, Glu109 and Asp107, single disulphide bridge between Cys32 and Cys61 and three calcium binding site residues Pro9, Gly45 and Asp207. Presence of calcium ion improves the thermal stability of SU40 β-1,3-1,4-glucanase. Molecular dynamics simulation studies revealed that the absence of calcium ion fluctuate the active site residues which are responsible for thermostability. The high catalytic activity and its stability to temperature, pH and metal ions indicated that the enzyme β-1,3-1,4-glucanase by B. subtilis SU40 is a good candidate for biotechnological applications.
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http://dx.doi.org/10.6026/97320630009958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867647PMC
January 2014

Molecular modeling, dynamics, and an insight into the structural inhibition of cofactor independent phosphoglycerate mutase isoform 1 from Wuchereria bancrofti using cheminformatics and mutational studies.

J Biomol Struct Dyn 2013 22;31(7):765-78. Epub 2012 Aug 22.

Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry, 605014, India.

Phosphoglycerate mutase catalyzes the interconversion between 2-phosphoglycerate and 3-phosphoglycerate in the glycolytic and gluconeogenic pathways. They exist in two unrelated forms, that is either cofactor (2,3-diphosphoglycerate) dependent or cofactor-independent. These two enzymes have no similarity in amino acid sequence, tertiary structure, and in catalytic mechanism. Wuchereria bancrofti (WB) contains the cofactor-independent form, whereas other organisms can possess the dependent form or both. Since, independent phosphoglycerate mutase (iPGM) is an essential gene for the survival of nematodes, and it has no sequence or structural similarity to the cofactor-dependent phosphoglycerate mutase found in mammals, it represents an attractive drug target for the filarial nematodes. In this current study, a putative cofactor-iPGM gene was identified in the protein sequence of the WB. In the absence of crystal structure, a three-dimensional structure was determined using the homology modeling approximation, and the most stable protein conformation was identified through the molecular dynamics simulation studies, using GROMACS 4.5. Further, the functional or characteristic residues were identified through the sequence analysis, potential inhibitors were short-listed and validated, and potential inhibitors were ranked using the cheminformatics and molecular dynamics simulations studies, Prime MM-GBSA approach, respectively.
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http://dx.doi.org/10.1080/07391102.2012.709460DOI Listing
November 2013

Neutralization of haemorrhagic activity of viper venoms by 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile.

Basic Clin Pharmacol Toxicol 2011 Oct 27;109(4):292-9. Epub 2011 Jun 27.

Department of Studies in Biochemistry, University of Mysore, Mysore, Karnataka, India.

Viper envenomation undeniably induces brutal local manifestations such as haemorrhage, oedema and necrosis involving massive degradation of extracellular matrix at the bitten region and many a times results in dangerous systemic haemorrhage including pulmonary shock. Snake venom metalloproteases (SVMPs) are being considered to be the primary culprits for the venom-induced haemorrhage. As a consequence, the venom researchers and medical practitioners are in deliberate quest of SVMP inhibitors. In this study, we evaluated the inhibitory effect of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (DFD) on viper venom-induced haemorrhagic and PLA(2) activities. DFD effectively neutralized the haemorrhagic activity of the medically important viper venoms such as Echis carinatus, Echis ocelatus, Echis carinatus sochureki, Echis carinatus leakeyi and Crotalus atrox in a dose-dependent manner. The histological examinations revealed that the compound DFD effectively neutralizes the basement membrane degradation, and accumulation of inflammatory leucocytes at the site of Echis carinatus venom injection further confirms the inhibition of haemorrhagic activity. In addition, DFD dose dependently inhibited the PLA(2) activities of Crotalus atrox and E. c. leakeyi venoms. According to the docking studies, DFD binds to hydrophobic pocket of SVMP with the ki of 19.26 × 10(-9) (kcal/mol) without chelating Zn(2+) in the active site. It is concluded that the clinically approved inhibitors of haemorrhagins could be used as a potent first-aid agent in snakebite management. Furthermore, a high degree of structural and functional homology between SVMPs and their relatives, the MMPs, suggests that DFD analogues may find immense value in the regulation of multifactorial pathological conditions like inflammation, cancer and wound healing.
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http://dx.doi.org/10.1111/j.1742-7843.2011.00725.xDOI Listing
October 2011

Structural basis for antagonism by suramin of heparin binding to vaccinia complement protein.

Biochemistry 2005 Aug;44(32):10757-65

Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, Birmingham, Alabama 35294-4400, USA.

Suramin is a competitive inhibitor of heparin binding to many proteins, including viral envelope proteins, protein tyrosine phosphatases, and fibroblast growth factors (FGFs). It has been clinically evaluated as a potential therapeutic in treatment of cancers caused by unregulated angiogenesis, triggered by FGFs. Although it has shown clinical promise in treatment of several cancers, suramin has many undesirable side effects. There is currently no experimental structure that reveals the molecular interactions responsible for suramin inhibition of heparin binding, which could be of potential use in structure-assisted design of improved analogues of suramin. We report the structure of suramin, in complex with the heparin-binding site of vaccinia virus complement control protein (VCP), which interacts with heparin in a geometrically similar manner to many FGFs. The larger than anticipated flexibility of suramin manifested in this structure, and other details of VCP-suramin interactions, might provide useful structural information for interpreting interactions of suramin with many proteins.
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http://dx.doi.org/10.1021/bi050401xDOI Listing
August 2005
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