Browsing by Author "Raj Kumar Koiri"

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Activation of p53 mediated glycolytic inhibition-oxidative stress-apoptosis pathway in Dalton's lymphoma by a ruthenium (II)-complex containing 4-carboxy N-ethylbenzamide
(Elsevier, 2015) Raj Kumar Koiri; Surendra Kumar Trigun; Lallan Mishra
There is a general agreement that most of the cancer cells switch over to aerobic glycolysis (Warburg effect) and upregulate antioxidant enzymes to prevent oxidative stress induced apoptosis. Thus, there is an evolving view to target these metabolic alterations by novel anticancer agents to restrict tumor progression in vivo. Previously we have reported that when a non toxic dose (10 mg/kg bw i.p.) of a novel anticancer ruthenium(II)-complex containing 4-carboxy N-ethylbenzamide; Ru(II)-CNEB, was administered to the Dalton's lymphoma (DL) bearing mice, it regressed DL growth by inducing apoptosis in the DL cells. It also inactivated M4-LDH (M4-lactate dehydrogenase), an enzyme that drives anaerobic glycolysis in the tumor cells. In the present study we have investigated whether this compound is able to modulate regulation of glycolytic inhibition-apoptosis pathway in the DL cells in vivo. We observed that Ru(II)-CNEB could decline expression of the inducible form of 6-phosphofructo-2-kinase (iPFK2: PFKFB3), the master regulator of glycolysis in the DL cells. The complex also activated superoxide dismutase (the H2O2 producing enzyme) but declined the levels of catalase and glutathione peroxidase (the two H2O2 degrading enzymes) to impose oxidative stress in the DL cells. This was consistent with the enhanced p53 level, decline in Bcl2/Bax ratio and activation of caspase 9 in those DL cells. The findings suggest that Ru(II)-CNEB is able to activate oxidative stress-apoptosis pathway via p53 (a tumor supressor protein) mediated repression of iPFK2, a key glycolytic regulator, in the DL cells in vivo. © 2015 Elsevier B.V. and Société franc¸aise de biochimie et biologie Moléculaire (SFBBM). All rights reserved.
Cytotoxic activity, cell imaging and photocleavage of DNA induced by a Pt(ii) cyclophane bearing 1,2 diamino ethane as a terminal ligand
(2011) Niraj Kumari; Brajesh Kumar Maurya; Raj Kumar Koiri; Surendra Kumar Trigun; Srikrishna Saripella; Michael P. Coogan; Lallan Mishra
A Pt II complex [{Pt(en)L} 2]·4PF 6 (Ptcyp) (LH 2 = N,N′-bis(salicylidene)-p-phenylenediamine, en = 1,2-diamino ethane) shows high cytotoxicity against HeLa cells (IC 50 - 11.5 μM) and against Dalton's lymphoma (DL) cells (IC 50 - 0.65 nM); UV-vis titration of Ptcyp with calf thymus DNA (CT-DNA) demonstrated its DNA binding, which could be further quantified by competitive fluorescence titration of DNA, Ptcyp and ethidium bromide. Circular dichroism studies suggest that Ptcyp interacts with CT-DNA by intercalation in an aqueous medium containing a minimum amount of DMSO. Agarose gel electrophoresis showed that Ptcyp is able to convert a supercoiled pBR322 plasmid DNA into a nicked circular DNA in DMSO, but to a much lower extent in an aqueous medium. However, with UV irradiation, Ptcyp is able to cause concentration-dependent nicking of supercoiled DNA in an aqueous medium. These findings indicate the DNA binding and UV exposure-dependent DNA cleavage properties of Ptcyp. Cell imaging studies using the HeLa cell line carried out in the presence of Ptcyp represent one of the first examples of Pt complexes applied as fluorophores in cell imaging and strongly support its interaction with DNA. © 2011 The Royal Society of Chemistry.
Lactate as a signaling molecule: Journey from dead end product of glycolysis to tumor survival
(Frontiers in Bioscience, 2019) Divya Rawat; Saurabh Kumar Chhonker; Rayees Ahmad Naik; Aditi Mehrotra; Surendra Kumar Trigun; Raj Kumar Koiri
Global metabolism of cancers exhibits a peculiar phenotype that is lactate acidosis (high lactate with acidic pH) in tumor microenvironment. Why tumor microenvironment becomes so responsive towards lactate is still not clear. In this review we have discussed lactate generation and recycling either exogenously, directly or indirectly by cancer cells via some transporters. Tumor cells in hypoxia use glucose rapidly and produce lactate while cells which have profuse oxygen supply take up lactate and use it for energy production which is referred as lactate shuttling between tumor cells. Escaping immune evasion which is also an emerging hallmark of cancer cells has also been discussed in this review with respect of lactate acidosis. © 2019 Frontiers in Bioscience. All Rights Reserved.
Metal Cu(II) and Zn(II) bipyridyls as inhibitors of lactate dehydrogenase
(2008) Raj Kumar Koiri; Surendra Kumar Trigun; Santosh Kumar Dubey; Santosh Singh; Lallan Mishra
Metal complex-protein interaction is an evolving concept for determining cellular targets of metallodrugs. Lacatate dehydrogenase (LDH) is critically implicated in tumor growth and therefore, considered to be an important target protein for anti-tumor metal complexes. Due to efficient biocompatibility of copper (Cu2+) and zinc (Zn2+), we synthesized CubpyAc 2 · H2O (Cu-bpy) and ZnbpyAc2 · H2O (Zn-bpy; where bpy = 2,2′ bipyridine, Ac = CH 3COO-) complexes and evaluated their interaction with and modulation of LDH in mouse tissues. The increasing concentration of both the complexes showed a significant shift in UV-Vis spectra of LDH. The binding constant data (Kc = 1 × 103 M-1 for Cu-bpy and 7 × 106 M-1 for Zn-bpy) suggested that Zn-bpy-LDH interaction is stronger than that of Cu-bpy-LDH. LDH modulating potential of the complexes were monitored by perfusing the mice tissues with non-toxic doses of Cu-bpy and Zn-bpy followed by activity measurement and analysis of LDH isozymes on non-denaturing polyacrylamide gel electrophoresis (PAGE). As compared to the control sets, Cu-bpy caused a significant decline (P < 0.05-0.001) in the activity of LDH in all the tissues studied. However, Zn-bpy showed inhibition of LDH only in liver (P < 0.01), kidney (P < 0.001) and heart (P < 0.01), but with no effect in spleen, brain and skeletal muscle tissues. PAGE analysis suggested that all the five LDH isozymes are equally sensitive to both the complexes in the respective tissues. The results suggest that Cu- and Zn-bpy are able to interact with and inhibit LDH, a tumor growth supportive target protein at tissue level. © 2007 Springer Science+Business Media BV.
Network-based drug discovery, anti-cancer molecular targets and therapeutic use of phytochemicals
(Bentham Science Publishers B.V., 2018) Raj Kumar Koiri; Aditi Mehrotra
[No abstract available]
Structural characterization and cytotoxicity studies of ruthenium(II)-dmso-chloro complexes of chalcone and flavone derivatives
(Elsevier Ltd, 2010) Rishikesh Prajapati; Santosh Kumar Dubey; Ruchi Gaur; Raj Kumar Koiri; Brajesh Kumar Maurya; Surendra Kumar Trigun; Lallan Mishra
A synthetic precursor cis-[RuIICl2(dmso)4] is complexed separately with 3-(4-benzyloxyphenyl)-1-(2-hydroxylphenyl)-prop-2-en-1-one (L1H) and 2-(4-benzyloxyphenyl)-3hydroxy-chromen-4-one (L2H). The resulting complexes are assigned the composition fac-[RuCl(S-dmso)3(L1)] 1 and fac-[RuCl(S-dmso)3(L2)] 2 using elemental analyses, FAB mass data and spectroscopic (IR, 1H NMR, UV-Vis, emission) spectral properties. The X-ray diffraction analysis shows that complexes self-associate through non-covalent interactions and provide 1D and 2D supramolecular structures. These complexes are assayed for their cytotoxicity studies on Dalton Lymphoma cell lines. © 2009 Elsevier Ltd. All rights reserved.
Targetting cancer with Ru(III/II)-phosphodiesterase inhibitor adducts: A novel approach in the treatment of cancer
(2013) Raj Kumar Koiri; Aditi Mehrotra; Surendra Kumar Trigun
Lack of specificity and normal tissue toxicity are the two major limitations faced with most of the anticancer agents in current use. Due to effective biodistribution and multimodal cellular actions, during recent past, ruthenium complexes have drawn much attention as next generation anticancer agents. This is because metal center of ruthenium (Ru) effectively binds with the serum transferrin and due to higher concentration of transferrin receptors on the tumor cells, much of the circulating Ru-transferrin complexes are delivered preferentially to the tumor site. This enables Ru-complexes to become tumor cell specific and to execute their anticancer activities in a somewhat targeted manner. Also, there are evidences to suggest that inhibition of phosphodiesterases leads to increased cyclic guanosine monophosphate (cGMP) level, which in turn can evoke cell cycle arrest and can induce apoptosis in the tumor cells. In addition, phosphodiesterase inhibition led increased cGMP level may act as a potent vasodilator and thus, it is likely to enhance blood flow to the growing tumors in vivo, and thereby it can further facilitate delivery of the drugs/compounds to the tumor site.Therefore, it is hypothesized that tagging PDE inhibitors (PDEis) with Ru-complexes could be a relevant strategy to deliver Ru-complexes-PDEi adduct preferentially to the tumor site. The Ru-complex tagged entry of PDEi is speculated to initially enable the tumor cells to become a preferential recipient of such adducts followed by induction of antitumor activities shown by both, the Ru-complex & the PDEi, resulting into enhanced antitumor activities with a possibility of minimum normal tissue toxicity due to administration of such complexes. © 2013 Elsevier Ltd.