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Biochemical Pharmacology (v.75, #12)
Atherosclerosis: A redox-sensitive lipid imbalance suppressible by cyclopentenone prostaglandins
by Lucila Ludmila Paula Gutierrez; Alexandre Maslinkiewicz; Rui Curi; Paulo Ivo Homem de Bittencourt Jr. (pp. 2245-2262).
Disorders concerning the metabolism of plasma and intracellular lipids are hallmarks of atherosclerosis. However, failures in proper control of intracellular cholesterol balance, rather than simple cholesterol overloading due to augmented uptake, could fuel atherogenesis. Therefore, the understanding of atherosclerosis-associated lipid alterations, which feed an inflammatory microenvironment in the arterial wall, requires the meticulous investigation of several aspects of lipid synthesis, uptake and export from cells. In this regard, the presence of reactive cysteines in transcription factors and key enzymes of lipid metabolism may dictate cholesterol accumulation, and therefore the progression of vascular disease. The strong inhibitory effect of cysteine-reactant anti-inflammatory cyclopentenone prostaglandins (CP-PGs) over atherosclerosis progression in vivo (LipoCardium technology) symbolizes a new concept of atherosclerosis and its treatment. Results from this laboratory and those from other research groups have unraveled a novel facet in prostaglandin research in that CP-PGs may act as redox signals that guide lipid metabolism in atherosclerosis. By modifying enzymes ( e.g., HMG-CoA reductase, ACAT and cholesteryl ester hydrolases) and transcription factors ( e.g., NF-κB and Keap1) involved in inflammation and lipid metabolism, CP-PGs (especially those of A-series) induce pivotal changes in glutathione and lipid metabolism that completely arrest atherosclerosis progression. Hence, pharmacological manipulation of lipid metabolism by CP-PGs may be a novel and invaluable strategy for treating atherosclerosis. Also, a better understanding of why CP-PGs do not resolve inflammation physiologically may explain many unsolved questions and yield insights into atherogenesis and its termination.
Keywords: Abbreviations; ABC; ATP-binding cassette; ACAT; acyl-coenzyme A:cholesterol acyltransferase; AMPK; 5′-adenosine monophosphate-dependent protein kinase; AMPKK; AMPK kinase; AP-1; activator protein-1; Apo; apolipoprotein; ARE; antioxidant-responsive element; CEH; cholesteryl ester hydrolase; COX; cyclooxygenase; CP-PG; cyclopentenone prostaglandin; FAS; fatty acid synthase; G6PDH; glucose-6-phosphate dehydrogenase; γ-GCS; γ-glutamylcysteine synthetase; GSPx; glutathione peroxidase; GSRd; glutathione disulfide reductase; GST; glutathione; S; -transferase; HDL; high-density lipoprotein; HMG-CoA reductase; 3-hydroxy-3-methylglutaryl-coenzyme A reductase; hsp; heat-shock protein; ICAM-1; intercellular adhesion molecule-1; Keap1; Kelch-like ECH-associated protein-1; LDL; low-density lipoprotein; MAPK; mitogen-activated protein kinase; MRP/GS-X pump ATPase; multidrug resistance-associated protein/glutathione; S; -conjugate export ATPase; NF-κB; nuclear factor κB; NOS; nitric oxide synthase; Nrf2; nuclear factor-erythroid 2 p45-related factor 2; NSAID; non-steroidal anti-inflammatory drug; oxLDL; oxidized low-density lipoprotein; PG; prostaglandin; 15d-PGJ; 2; 15-deoxy-Δ; 12,14; -PGJ; 2; PPARγ; nuclear factor peroxisome proliferators-activated receptor; RLIP76/GS-X pump; the 76-kDa Ral-binding protein-1 (RalBP1), stress-responsive glutathione; S; -conjugate export ATPase; ROS/RNS; reactive oxygen/nitrogen species; SR; scavenger receptor; SRE; sterol-regulatory element; SREBP; sterol-regulatory element binding protein; TGFβ; transforming growth factor-β; TNFα; tumor necrosis factor-α; VCAM-1; vascular cell adhesion molecule-1; VLDL; very-low density lipoproteinAtherosclerosis; Cyclopentenone prostaglandins; Reactive cysteines; 3-Hydroxy-3-methylglutaryl-coenzyme A reductase; Cholesterol metabolism
Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases
by James P. Hardwick (pp. 2263-2275).
The cytochrome P450 gene 4 family (CYP4) consists of a group of over 63 members that ω-hydroxylate the terminal carbon of fatty acids. In mammals, six subfamilies have been identified and three of these subfamily members show a preference in the metabolism of short (C7–C10)-CYP4B, medium (C10–C16)-CYP4A, and long (C16–C26)-CYP4F, saturated, unsaturated and branched chain fatty acids. These ω-hydroxylated fatty acids are converted to dicarboxylic acids, which are preferentially metabolized by the peroxisome β-oxidation system to shorter chain fatty acids that are transported to the mitochondria for complete oxidation or used either to supply energy for peripheral tissues during starvation or in lipid synthesis. The differential regulation of the CYP4A and CYP4F genes during fasting, by peroxisome proliferators and in non-alcoholic fatty liver disease (NAFLD) suggests different roles in lipid metabolism. The ω-hydroxylation and inactivation of pro-inflammatory eicosanoids by members of the CYP4F subfamily and the association of the CYP4F2 and CYP4F3 genes with inflammatory celiac disease indicate an important role in the resolution of inflammation. Several human diseases have been genetically linked to the expression CYP4 gene polymorphic variants, which may link human susceptibility to diseases of lipid metabolism and the activation and resolution phases of inflammation. Understanding how the CYP4 genes are regulated during the fasting and feeding cycles and by endogenous lipids will provide therapeutic avenues in the treatment of metabolic disorders of lipid metabolism and inflammation.
Keywords: Abbreviations; SCFA; short chain fatty acid (C; 7; –C; 9; ); MCFA; medium chain fatty acid(C; 10; –C; 16; ); LCFA; long chain fatty acid (C; 18; –C; 22; ); VLCFA; very long chain fatty acid (>C; 22; ); ACC1; acetyl-CoA carboxylase; ACSI; acetate CoA synthetase; ACOX; acyl-CoA oxidase; ACOT; acyl-CoA thioesterase; b; 5; cytochrome; b; 5; SCD-1; stearoyl CoA desarturase 1; LBP; L-Bifunctional protein; DBP; D-Bifunctional protein; TG; triglyceride; PL; phospholipid; CE; cholesterol ester; WE; wax ester; VLDL; very low density lipoprotein; steatosis; fatty liver; steatohepatitis; fatty liver with inflammation; NAFLD; non-alcoholic fatty liver disease; NASH; non-alcoholic steatohepatitis; 20-HETE; 20-hydroxyeicosatetraenoic acid; ωHEET; 20-hydroxyeicosatrenoic acid; PP; peroxisome proliferators; HNF4α; hepatocyte nuclear factor 4; PPARα; peroxisome proliferator activated receptor α; SREBP; sterol regulatory element binding protein; ChREBP; carbohydrate responsive element binding protein; LTB; 4; leukotriene B; 4; APR; acute phase response; PUFA; polyunsaturated fatty acids; LPS; lipopolysaccharide; IL-1; interleukin-1; IL-8; interleukin-8; L-PK; liver pyruvate kinase; CPT1; carnitine palmitoyltransferase1; ROS; reactive oxygen speciesCytochrome P450; Fatty acids; Metabolism; Inflammation; Metabolic disorders; Non-alcoholic fatty liver disease; Steatosis; Steatohepatitis; PPARα; HNF4α; Peroxisome
Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI
by Mi-Ran Choi; Farhad Najafi; Ahmad R. Safa; Hannes C.A. Drexler (pp. 2276-2288).
Proteasome inhibitors display potent anti-neoplastic and anti-angiogenic properties both in vitro and in vivo. The mechanisms, however, by which proteasome inhibitors kill tumor cells are still fairly elusive as is the molecular basis of resistance to treatment. To address these questions, we employed a high-throughput Western blotting procedure to analyze changes in a subproteome of ∼800 proteins in the promyelocytic leukemia cell line HL-60 upon treatment with the proteasome inhibitor PSI (Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde) and correlated the changes of selected target proteins with the changes in two multidrug-resistant HL-60 variants. In total, 105 proteins were upregulated more than 1.5-fold after PSI treatment, while 79 proteins were downregulated. Activation of caspases-3 and -8, modulation of members of the Bcl-2 family as well as stimulation of stress signaling pathways was prominent during HL-60 apoptosis. We also identified changes in the abundance of proteins previously not known to be affected by proteasome inhibitors. In contrast, two multidrug-resistant HL-60 cell lines, overexpressing either MRP1 or P-glycoprotein were largely resistant to PSI-induced apoptosis and could not be resensitized by the pharmacological inhibitors of the drug efflux pumps MK571 or PSC833. Drug resistance was also independent of the upregulation of Bad. Overexpression of multidrug resistance proteins, P-glycoprotein and MRP-1 is thus not sufficient to explain resistance of HL-60 cells to treatment with proteasome inhibitor PSI, which remains more closely related to a low level of Bax expression and to the inability to activate JNK. Alternative routes to the acquisition of resistance to PSI have therefore to be considered.
Keywords: Proteasome inhibitor; Apoptosis; Multidrug resistance; P-gp; MDR-1
Magnolol elicits activation of the extracellular signal-regulated kinase pathway by inducing p27KIP1-mediated G2/M-phase cell cycle arrest in human urinary bladder cancer 5637 cells
by Se-Jung Lee; Young-Hwa Cho; Keerang Park; Eun-Jung Kim; Kyung-Hwan Jung; Sung-Soo Park; Wun-Jae Kim; Sung-Kwon Moon (pp. 2289-2300).
Magnolol has been reported to play a role in antitumor activity. However, the relevant pathway integrating cell cycle regulation and signaling pathways involved in growth inhibition in cancer cells remains to be identified. In the present study, magnolol treatment of these cells resulted in significant dose-dependent growth inhibition together with apoptosis, G1- and G2/M-phase cell cycle arrest at a 60μM (IC50) dose in 5637 bladder cancer cells. In addition, magnolol treatment strongly induced p27KIP1 expression, and down-regulated expression of cyclin-dependent kinases (CDKs) and cyclins. Moreover, treatment with magnolol-induced phosphorylation of ERK, p38 MAP kinase, and JNK. Among the pathway inhibitors examined, only PD98059, an ERK-specific inhibitor, blocked magnolol-dependent p27KIP1 expression. Blockade of ERK function consistently reversed magnolol-mediated inhibition of cell proliferation and decreased G2/M cell cycle proteins, but not G1 cell cycle proteins. Furthermore, magnolol treatment increased both Ras and Raf activation. Transfection of cells with dominant negative Ras (RasN17) and Raf (RafS621A) mutant genes suppressed magnolol-induced ERK activity and p27KIP1 expression. Finally, the magnolol-induced reduction in cell proliferation and G2/M cell cycle proteins was also abolished in the presence of RasN17 and RafS621A mutant genes. These data demonstrate that the Ras/Raf/ERK pathway participates in p27KIP1 induction, leading to a decrease in the levels of cyclin B1/Cdc2 complexes and magnolol-dependent inhibition of cell growth. Overall, these novel findings concerning the molecular mechanisms of magnolol in 5637 bladder cancer cells provide a theoretical basis for therapeutic treatment of malignancies.
Keywords: Magnolol; Bladder cancer 5637 cells; G2/M-phase cell cycle arrest; p27KIP1
Characterization of isoprostane signaling: Evidence for a unique coordination profile of 8-iso-PGF2α with the thromboxane A2 receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets
by Fadi T. Khasawneh; Jin-Sheng Huang; Fozia Mir; Subhashini Srinivasan; Chinnaswamy Tiruppathi; Guy C. Le Breton (pp. 2301-2315).
Since isoprostanes are thought to participate in the pathogenesis of thrombosis, presumably through their interaction with thromboxane receptors (TPRs), we examined the ability of 8-iso-PGF2α to bind/signal through TPRs. Using TPR expressing HEK cells, it was found that 8-iso-PGF2α mobilized calcium and bound TPRs with a dissociation constant ( Kd) of 57nM. Interestingly, site-directed-mutagenesis revealed that 8-iso-PGF2α has a unique coordination profile with TPRs. Thus, while Phe184 and Asp193 are shared by both 8-iso-PGF2α and classical TPR ligands, Phe196 was found to be required only for 8-iso-PGF2α binding. Functional studies also revealed interesting results. Namely, that 8-iso-PGF2α signals in human platelets through both a stimulatory (TPR-dependent) and an inhibitory (cAMP-dependent) pathway. Consistent with the existence of two signaling pathways, platelets were also found to possess two separate binding sites for 8-iso-PGF2α. While the stimulatory site is represented by TPRs, the second cAMP inhibitory site is presently unidentified, but does not involve receptors for PGI2, PGD2 or PGE2. In summary, these studies provide the first documentation that: (1) 8-iso-PGF2α coordinates with Phe184, Asp193 and Phe196 on platelet TPRs; (2) Phe196 serves as a unique TPR binding site for 8-iso-PGF2α; (3) 8-iso-PGF2α signals through both stimulatory and inhibitory pathways in platelets; (4) 8-iso-PGF2α inhibits human platelet activation through a cAMP-dependent mechanism; (5) 8-iso-PGF2α interacts with platelets at two separate binding sites. Collectively, these results provide evidence for a novel isoprostane function in platelets which is mediated through a cAMP-coupled receptor.
Keywords: Abbreviations; AA; arachidonic acid; AC; adenylate cyclase; cAMP; adenosine 3′,5′-cyclic monophosphate; C-EL2; C-terminus of the second extracellular loop; HEK; human embryonic kidney; IPR; PGI; 2; receptor; DPR; PGD; 2; receptor; EP; 2; R; PGE; 2; receptor; PRP; platelet rich plasma; ROCK; Rho-kinase; TRAP-PAR1; thrombin receptor-activating peptide 1; RT; room temperature; SC; shape change; TM5; the fifth transmembarne domain; TPR; thromboxane A; 2; receptor; WT; wild type; AH 6809; 6-isopropoxy-9-oxoxanthene-2-carboxylic acid; BW A868C; 3-((2-cyclohexyl-2-hydroxyethyl)amino)-2,5-dioxo-1-(phenylmethyl)-4-benzyl-4-imidazolidine-heptanoic acid; CAY10441; (4,5-dihydro-1; H; -imidazol-2-yl)-[4-(4-isopropoxy benzyl) phenyl] amine; 8-iso-PGF; 2α; 9α, 11α, 15; S; -trihydroxy-(8β)-Prosta-5; Z; ,13; E; -dien-1-oic acid; SQ29,548; [1; S; -[1α,2β(5; Z; ),3β,4α]]-7-[3-[[2-[(phenyl-amino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; U46619; 15(; S; )-hydroxy-11,9-epoxymethanoprosta-5; Z; ,13; E; -dienoic acidThromboxane A; 2; receptor; Isoprostanes; Platelet; Site-directed mutagenesis; Radioligand binding; Calcium mobilization
Homeostasis of retinol in lecithin: Retinol acyltransferase gene knockout mice fed a high retinol diet
by Limin Liu; Xiao-Han Tang; Lorraine J. Gudas (pp. 2316-2324).
We analyzed the retinoid levels and gene expression in various tissues after wild-type (Wt) and lecithin:retinol acyltransferase ( LRAT−/−) knockout mice were fed a high retinol diet (250IU/g). As compared to Wt, LRAT−/− mice exhibited a greater and faster increase in serum retinol concentration (mean±S.D., Wt, 1.3±0.2μM to 1.5±0.3μM in 48h, p>0.05; LRAT−/−, 1.3±0.2μM to 2.2±0.3μM in 48h, p<0.01) and a higher level of retinol in adipose tissue (17.2±2.4pmol/mg in Wt vs. 34.6±8.0pmol/mg in LRAT−/−). In the small intestines of Wt mice higher levels of retinol (96.4±13.0pmol/mg in Wt vs. 13.7±7.6pmol/mg in LRAT−/−) and retinyl esters (2493.4±544.8pmol/mg in Wt vs. 8.2±2.6pmol/mg in LRAT−/−) were detected. More retinol was detected in the feces of LRAT−/− mice (69.3±32.6pmol/mg in LRAT−/− vs. 24.1±8.6pmol/mg in Wt). LRAT mRNA levels increased in the lungs, small intestines, and livers of Wt mice on the high retinol diet, while CYP26A1 mRNA levels increased greatly only in the LRAT−/− mice. After 4 weeks, no significant differences between Wt mice and LRAT−/− mice were observed in either the serum retinol level or in the prevalence of Goblet cells in jejunal crypts. Our data indicate that the LRAT−/− mice maintain the homeostasis of retinol as the dietary retinol increases by increasing the excretion of retinol from the gastrointestinal tract, increasing the distribution of retinol to adipose tissue, and enhancing the catabolism by CYP26A1. We show that LRAT plays a role in maintaining a stable serum retinol concentration when dietary retinol concentration fluctuates.
Keywords: Abbreviations; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; GI; gastrointestinal; HPLC; high-performance liquid chromatography; IU; International Unit; LRAT; lecithin:retinol acyltransferase; PBS; phosphate buffered saline; RA; all-; trans; retinoic acid; RARs; retinoic acid receptors; RBP4; retinol-binding protein 4; Rol; retinol; REs; retinyl esters; Wt; wild-typeLRAT; Gene knockout mice; Retinol; Retinyl ester; Retinol absorption; Metabolism; Cytochrome P450
C-terminal mini-PEGylation of glucose-dependent insulinotropic polypeptide exhibits metabolic stability and improved glucose homeostasis in dietary-induced diabetes
by Victor A. Gault; Barry D. Kerr; Nigel Irwin; Peter R. Flatt (pp. 2325-2333).
Glucose-dependent insulinotropic polypeptide has been proposed as a potential therapeutic for type 2 diabetes, however, efforts to bring forward this drug have been hindered due to its short circulating half-life. We have adopted a novel strategy to increase potency and prolong GIP action through C-terminal mini-PEGylation (GIP[mPEG]). In contrast to GIP, GIP[mPEG] was resistant to dipeptidylpeptidase-IV (DPP-IV) up to and including 24h. Both GIP[mPEG] and GIP concentration-dependently stimulated cAMP production (EC50 6.6 and 0.7nM, respectively) and insulin secretion ( p<0.01 to p<0.001) in pancreatic BRIN-BD11 cells. Acute injection of GIP[mPEG] together with glucose to high fat fed mice significantly lowered plasma glucose ( p<0.05) and increased plasma insulin responses ( p<0.05). Furthermore, GIP[mPEG] markedly lowered plasma glucose when administered 4–24h prior to a glucose load ( p<0.05). Daily administration of GIP[mPEG] for 20 days in high fat mice did not alter body weight, food intake or non-fasting plasma insulin, however, non-fasting plasma glucose concentrations were significantly lowered ( p<0.05). Moreover, glucose tolerance was significantly improved ( p<0.05) together with glucose-mediated plasma insulin responses ( p<0.05). Insulin sensitivity, pancreatic insulin content, triglyceride and adiponectin levels were not changed. In summary, these data demonstrate that C-terminal mini-PEGylation of GIP is a useful strategy to prolong metabolic stability and improve biological action thus representing a novel therapeutic option for type 2 diabetes.
Keywords: Dipeptidylpeptidase-IV (DPP-IV); Glucose-dependent insulinotropic polypeptide (GIP); GIP analogue; Glucose homeostasis; Insulin secretion; PEGylation; Mini-PEG [mPEG]
Specificity, affinity and efficacy of iota-conotoxin RXIA, an agonist of voltage-gated sodium channels NaV1.2, 1.6 and 1.7
by Brian Fiedler; Min-Min Zhang; Oga Buczek; Layla Azam; Grzegorz Bulaj; Raymond S. Norton; Baldomero M. Olivera; Doju Yoshikami (pp. 2334-2344).
The excitotoxic conopeptide ι-RXIA induces repetitive action potentials in frog motor axons and seizures upon intracranial injection into mice. We recently discovered that ι-RXIA shifts the voltage-dependence of activation of voltage-gated sodium channel NaV1.6 to a more hyperpolarized level. Here, we performed voltage-clamp experiments to examine its activity against rodent NaV1.1 through NaV1.7 co-expressed with the β1 subunit in Xenopus oocytes and NaV1.8 in dissociated mouse DRG neurons. The order of sensitivity to ι-RXIA was NaV1.6>1.2>1.7, and the remaining subtypes were insensitive. The time course of ι-RXIA-activity on NaV1.6 during exposure to different peptide concentrations were well fit by single-exponential curves that provided kobs. The plot of kobs versus [ι-RXIA] was linear, consistent with a bimolecular reaction with a Kd of ∼3μM, close to the steady-state EC50 of ∼2μM. ι-RXIA has an unusual residue, D-Phe, and the analog with an L-Phe instead, ι-RXIA[L-Phe44], had a two-fold lower affinity and two-fold faster off-rate than ι-RXIA on NaV1.6 and furthermore was inactive on NaV1.2. ι-RXIA induced repetitive action potentials in mouse sciatic nerve with conduction velocities of both A- and C-fibers, consistent with the presence of NaV1.6 at nodes of Ranvier as well as in unmyelinated axons. Sixteen peptides homologous to ι-RXIA have been identified from a single species of Conus, so these peptides represent a rich family of novel sodium channel-targeting ligands.
Keywords: Channel-activation; Conopeptide; Excitotoxin; Iota-conotoxin RXIA; Neurotoxin; Voltage-gated sodium channel
Role of Bax in quercetin-induced apoptosis in human prostate cancer cells
by Dae-Hee Lee; Miroslaw Szczepanski; Yong J. Lee (pp. 2345-2355).
The aim of this study was to investigate the effect of quercetin, a flavonoid, on the apoptotic pathway in a human prostate cell line (LNCaP). We observed that treatment of cells for 24h with quercetin-induced cell death in a dose-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in quercetin-treated cells. Treatment of LNCaP cells with an apoptosis inducing concentration of quercetin (100μM) resulted in a rapid decrease in the inhibitory Ser(473) phosphorylation of Akt leading to inhibition of its kinase activity. Quercetin treatment (100μM) also caused a decrease in Ser(136) phosphorylation of Bad, which is a downstream target of Akt. Protein interaction assay revealed that during treatment with quercetin, Bcl-xL dissociated from Bax and then associated with Bad. Our results also show that quercetin decreases the Bcl-xL:Bax ratio and increases translocation and multimerization of Bax to the mitochondrial membrane. The translocation is accompanied by cytochrome c release, and procaspases-3, -8 and -9 cleavage and increased poly(ADP-ribose) polymerase (PARP) cleavage. Similar results were observed in human colon cancer HCT116Bax+/+ cell line, but not HCT116Bax−/− cell line. Interestingly, at similar concentrations (100μM), quercetin treatment did not affect the viability or rate of apoptosis in normal human prostate epithelial cell line (PrEC) and rat prostate epithelial cell line (YPEN-1). Our results indicate that the apoptotic processes caused by quercetin are mediated by the dissociation of Bax from Bcl-xL and the activation of caspase families in human prostate cancer cells.
Keywords: Abbreviations; PAGE; polyacrylamide gel electrophoresis; PARP; poly(ADP-ribose) polymerase; PBS; phosphate-buffered saline; SDS; sodium dodecyl sulfate; DMSO; dimethyl sulfoxide; PI3K; phosphatidylinositol-3 kinase; TNF; tumor necrosis factorQuercetin; Apoptosis; Caspase; PI3K/Akt pathway; Cytochrome; c; Bax; Bad; Bcl-xL
Poly(ADPR)polymerase inhibition and apoptosis induction in cDDP-treated human carcinoma cell lines
by Nadia Gambi; Filomena Tramontano; Piera Quesada (pp. 2356-2363).
Poly(ADPR)polymerases’ (PARPs) inhibitors potentiate the cytotoxic effects of chemotherapeutic agents like alkylating compounds and TOPO I poisons, while their action in combination with cisplatin still needs investigation. In fact, one of the earliest responses to DNA single- or double-strand breaks is the synthesis of poly(ADP-ribose) (PAR) by PARPs; these enzymes are components of DNA repair machineries and substrates of caspases. Cisplatin (cDDP) yields intra- and inter-strand DNA cross-links and several proteins that recognise cDDP-induced DNA damage, such as p53, are also targets of poly(ADP-ribosyl)ation. We compared the effects of treatments with cDDP and the PARPs inhibitor PJ34 in p53 mutated carcinoma cell lines (HeLa, KB, HT29) that exhibited differential sensitivities to the drugs, in terms of cell growth inhibition and onset of apoptosis. In cDDP-resistant HT29 cells we determined: (i) PJ34 potentiation of cDDP-induced cell growth inhibition; (ii) an increment of PARP-1 automodification following cDDP treatment. In cDDP-sensitive HeLa cells, we found that the drug induced apoptotic cell death associated with caspase-dependent PARP-1 proteolysis.
Keywords: Cisplatin (cDDP); PARP-1; PJ34 inhibitor; p53; Carcinoma cells
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