title: Activation of p53 mediated glycolytic inhibition-oxidative stress-apoptosis pathway in Dalton's lymphoma by a ruthenium (II)-complex containing 4-carboxy N-ethylbenzamide.
abstract: 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.
authors.affiliation: Department of Zoology, Dr. Harisingh Gour Central University, Sagar, Madhya Pradesh 470003, India.
authors.forename: Raj Kumar
authors.initials: RK
authors.lastname: Koiri
authors.affiliation: Biochemistry Section, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India. Electronic address: sktrigun@gmail.com.
authors.forename: Surendra Kumar
authors.initials: SK
authors.lastname: Trigun
authors.affiliation: Department of Chemistry, Banaras Hindu University, Varanasi, Uttar Padesh 221005, India.
authors.forename: Lallan
authors.initials: L
authors.lastname: Mishra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008223:Lymphoma / Q000473:pathology*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D025481:Phosphofructokinase-2 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D006861:Hydrogen Peroxide; D007773:Lactates; D025481:Phosphofructokinase-2; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D016159:Tumor Suppressor Protein p53; D000099156:Superoxide Dismutase 2; C000606290:SOD1 protein, human; C579797:bis(2,2'-bipyridine)(4-carboy N-ethylbenzamide)ruthenium(II); C000606291:Sod1 protein, mouse
keywords: Apoptotic factors; LDH; PFKFB3; Ruthenium; p53