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Biochemical Pharmacology (v.74, #11)

Editorial Advisory Board (pp. iii).

Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy by Sandra Liekens; Annelies Bronckaers; Maria-Jésus Pérez-Pérez; Jan Balzarini (pp. 1555-1567).

Thymidine phosphorylase (TP) is a key enzyme in the pyrimidine nucleoside salvage pathway, but it also recognizes and inactivates various anti-cancer chemotherapeutic agents. Moreover, TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF), an angiogenic factor with anti-apoptotic properties. Increased expression of PD-ECGF/TP is found in many tumor and stromal cells, and elevated TP levels are associated with aggressive disease and/or poor prognosis. Thus, progression and metastasis of TP-expressing tumors might be abrogated by TP inhibitors that are used as single agents or in combination with (TP-sensitive) nucleoside analogues. On the other hand, increased TP activity in tumors may be exploited for the tumor-specific activation of fluoropyrimidine prodrugs, such as capecitabine. This review will focus on the different biological activities of PD-ECGF/TP and their implications for cancer progression and treatment.

Keywords: Abbreviations; CAM; chick chorioallantoic membrane; 2dR1P; 2-deoxy-; d; -ribose-1-phosphate; DFUR; 5′-deoxy-5-fluorouridine; FdUrd; 5-fluorodeoxyuridine; 5FU; 5-fluorouracil; HIF-1α; hypoxia-inducible factor-1α; IC; ₅₀; 50% inhibitory concentration; IFN; interferon; IL-8; interleukin-8; MMP; matrix metalloproteinase; MNGIE; mitochondrial neurogastrointestinal encephalomyopathy; PD-ECGF; platelet-derived endothelial cell growth factor; RA; rheumatoid arthritis; TAM; tumor-associated monocytic cell; TFT; trifluorothymidine; TNF-α; tumor necrosis factor-α; TP; thymidine phosphorylase; UP; uridine phosphorylase; VEGF; vascular endothelial growth factorAngiogenesis; Metastasis; 5-Fluorouracil; Nucleoside metabolism; PD-ECGF; Thymidine phosphorylase

Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells by Valentina Cecchinato; Raffaella Chiaramonte; Monica Nizzardo; Brunella Cristofaro; Andrea Basile; Gajanan V. Sherbet; Paola Comi (pp. 1568-1574).

Resveratrol (RES) is a natural occurring phytoalexin that has been shown to have chemopreventive activity. Resveratrol acts both by suppressing cell proliferation and inducing apoptosis in a variety of cancer cell lines. In this study, we show that RES induces apoptosis in MOLT-4 acute lymphoblastic leukaemia cells by modulating three different pathways that regulate cells survival and cell death. We show for the first time that RES inhibits the survival signalling pathways Notch and their down stream effector and modulates the operation of interacting signalling systems. It induces an increase in the levels of the pro-apoptotic proteins p53, its effector p21waf and Bax. We also show that RES inhibits the PI3K/Akt pathway and activates Gsk-3β. The data presented here demonstrate unequivocally that RES induces apoptosis by inhibiting the Notch pathway and markedly influencing the operation of the interacting apoptosis pathways mediated by p53 and PI3K/Akt. These data support findings from other laboratories that have suggested the use of RES as a chemopreventive agent. Here, we have identified potential signalling pathways influenced by RES and this could lead to the identification of the targets of RES-induced apoptosis and growth control.

Keywords: Resveratrol; Acute lymphoblastic leukemia; PI3K; p53; Apoptosis; Bax; Gsk

Anti-tumor potential of 15,16-dihydrotanshinone I against breast adenocarcinoma through inducing G1 arrest and apoptosis by Sun-Lung Tsai; Fat-Moon Suk; Chun-I. Wang; Der-Zen Liu; Wen-Chi Hou; Pei-Jung Lin; Ling-Fang Hung; Yu-Chih Liang (pp. 1575-1586).

Chemotherapeutic drugs are usually designed to induce cancer cell death via cell cycle arrest and/or apoptosis pathways. In this study, we used the chemical drug 15,16-dihydrotanshinone I (DHTS) to inhibit breast cancer cell proliferation and tumor growth, and investigate the underlying molecular mechanisms. Human breast cancer cell lines MCF-7 and MDA-MB-231 were both used in this study, and DHTS was found to significantly decrease cell proliferation by a dose-dependent manner in both cells. Flow cytometry indicated that DHTS induced G1 phase arrest in synchronous MCF-7 and MDA-MB-231 cells. When analyzing the expression of cell cycle-related proteins, we found that DHTS reduced cyclin D1, cyclin D3, cyclin E, and CDK4 expression, and increased CDK inhibitor p27 expression in a dose-dependent manner. In addition, DHTS inhibited the kinase activities of CDK2 and CDK4 by an immunocomplex kinase assay. In addition, DHTS also induced apoptosis in both cells through mainly mitochondrial apoptosis pathways. We found that DHTS decreased the anti-apoptotic protein Bcl-xL level and increased the loss of mitochondria membrane potential and the amount of cytochrome c released. Moreover, DHTS activated caspase-9, caspase-3, and caspase-7 and caused cell apoptosis. The fact that DHTS-induced apoptosis could be blocked by pretreating cells with pan-caspase inhibitor confirmed that it is mediated through activation of the caspase-3-dependent pathway. In a nude mice xenograft experiment, DHTS significantly inhibited the tumor growth of MDA-MB-231 cells. Taken together, these results suggest that DHTS can inhibit human breast cancer cell proliferation and tumor growth, and might have potential chemotherapeutic applications.

Keywords: Abbreviations; DHTS; 15,16-dihydrotanshinone I; TS; tanshinone I; CTS; cryptotanshinone I; CDK; cyclin-dependent kinase; Bcl-2; B-cell leukemia/lymphoma 2; APAF-1; apoptotic protease activity factor-1; PI; propidium iodide15,16-Dihydrotanshinone I; Breast cancer; Apoptosis; G1 arrest; Caspase; Cell cycle

The antiproliferative effects of phenoxodiol are associated with inhibition of plasma membrane electron transport in tumour cell lines and primary immune cells by P.M. Herst; T. Petersen; P. Jerram; J. Baty; M.V. Berridge (pp. 1587-1595).

Although the redox-active synthetic isoflavene, phenoxodiol, is in Phase 3 clinical trials for drug-resistant ovarian cancer, and in early stage clinical trials for prostate and cervical cancer, its primary molecular target is unknown. Nevertheless, phenoxodiol inhibits proliferation of many cancer cell lines and induces apoptosis by disrupting FLICE-inhibitory protein, FLIP, expression and by caspase-dependent and -independent degradation of the X-linked inhibitor of apoptosis, XIAP. In addition, phenoxodiol sensitizes drug-resistant tumour cells to anticancer drugs including paclitaxel, carboplatin and gemcitabine. Here, we investigate the effects of phenoxodiol on plasma membrane electron transport (PMET) and cell proliferation in human leukemic HL60 cells and mitochondrial gene knockout HL60ρ^o cells that exhibit elevated PMET. Phenoxodiol inhibited PMET by both HL60 (IC₅₀ 32μM) and HL60ρ^o (IC₅₀ 70μM) cells, and this was associated with inhibition of cell proliferation (IC₅₀ of 2.8 and 6.7μM, respectively), pan-caspase activation and apoptosis. Unexpectedly, phenoxodiol also inhibited PMET by activated murine splenic T cells (IC₅₀ of 29μM) as well as T cell proliferation (IC₅₀ of 2.5μM). In contrast, proliferation of WI-38 cells and HUVECs was only weakly affected by phenoxodiol. These results indicate that PMET may be a primary target for phenoxodiol in tumour cells and in activated T cells.

Keywords: Phenoxodiol; Anticancer drug; Mechanism of action; Plasma membrane electron transport; Apoptosis; T cells

The membrane permeable calcium chelator BAPTA-AM directly blocks human ether a-go-go-related gene potassium channels stably expressed in HEK 293 cells by Qiang Tang; Man-Wen Jin; Ji-Zhou Xiang; Min-Qing Dong; Hai-Ying Sun; Chu-Pak Lau; Gui-Rong Li (pp. 1596-1607).

BAPTA-AM is a well-known membrane permeable Ca²⁺ chelator. The present study found that BAPTA-AM rapidly and reversibly suppressed human ether a-go-go-related gene (hERG or Kv11.1) K⁺ current, human Kv1.3 and human Kv1.5 channel currents stably expressed in HEK 293 cells, and the effects were not related to Ca²⁺ chelation. The externally applied BAPTA-AM inhibited hERG channels in a concentration-dependent manner (IC₅₀: 1.3μM). Blockade of hERG channels was dependent on channel opening, and tonic block was minimal. Steady-state activation V_0.5 of hERG channels was negatively shifted by 8.5mV (from −3.7±2.8 of control to −12.2±3.1mV, P<0.01), while inactivation V_0.5 was negatively shifted by 6.1mV (from −37.9±2.0mV of control to −44.0±1.6mV, P<0.05) with application of 3μM BAPTA-AM. The S6 mutant Y652A and the pore helix mutant S631A significantly attenuated blockade by BAPTA-AM at 10μM causing profound blockade of wild-type hERG channels. In addition, BAPTA-AM inhibited hKv1.3 and hKv1.5 channels in a concentration-dependent manner (IC₅₀: 1.45 and 1.23μM, respectively), and the blockade of these two types of channels was also dependent on channel opening. Moreover, EGTA-AM was found to be an open channel blocker of hERG, hKv1.3, hKv1.5 channels, though its efficacy is weaker than that of BAPTA-AM. These results indicate that the membrane permeable Ca²⁺ chelator BAPTA-AM (also EGTA-AM) exerts an open channel blocking effect on hERG, hKv1.3 and hKv1.5 channels.

Keywords: BAPTA-AM; hERG; hKv1.3; hKv1.5; Open channel blocker

Effects of resveratrol, a grape polyphenol, on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells by Yuko Shinohara; Yumiko Toyohira; Susumu Ueno; Minhui Liu; Masato Tsutsui; Nobuyuki Yanagihara (pp. 1608-1618).

We report the effects of resveratrol, a polyphenol found in the skins of red grapes, on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. Resveratrol suppressed catecholamine secretion and²²Na⁺ and⁴⁵Ca²⁺ influx induced by acetylcholine, an agonist of nicotinic acetylcholine receptors, in a concentration-dependent manner (IC₅₀=20.4, 11.0, and 62.8μM, respectively). Resveratrol also inhibited catecholamine secretion induced by veratridine, an activator of voltage-dependent Na⁺ channels, and 56mM K⁺, an activator of voltage-dependent Ca²⁺ channels, at concentrations similar to those for⁴⁵Ca²⁺ influx. Resveratrol directly inhibited the current evoked by acetylcholine in Xenopus oocytes expressing α3β4 neuronal nicotinic acetylcholine receptors (IC₅₀=25.9μM). Furthermore, resveratrol (IC₅₀=5.32μM) attenuated¹⁴C-catecholamine synthesis induced by acetylcholine. The present findings suggest that resveratrol inhibits acetylcholine-induced catecholamine secretion and synthesis through suppressing ion influx in cultured bovine adrenal medullary cells.

Keywords: Abbreviations; KRP; Krebs–Ringer phosphate; Eagle's MEM; Eagle's minimum essential medium; PCA; perchloric acid; DMSO; dimethyl sulfoxideAdrenal medulla; Catecholamine secretion; Catecholamine synthesis; Nicotinic acetylcholine receptors; Phytoestrogen; Resveratrol

Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice by Rie Sasaki; Natsumi Nishimura; Hiromi Hoshino; Yasuka Isa; Maho Kadowaki; Takahito Ichi; Akihito Tanaka; Shin Nishiumi; Itsuko Fukuda; Hitoshi Ashida; Fumihiko Horio; Takanori Tsuda (pp. 1619-1627).

Adipocyte dysfunction is strongly associated with the development of obesity and insulin resistance. It is accepted that the regulation of adipocytokine expression is one of the most important targets for the prevention of obesity and improvement of insulin sensitivity. In this study, we have demonstrated that anthocyanin (cyanidin 3-glucoside; C3G) which is a pigment widespread in the plant kingdom, ameliorates hyperglycemia and insulin sensitivity due to the reduction of retinol binding protein 4 (RBP4) expression in type 2 diabetic mice. KK-A^y mice were fed control or control +0.2% of a C3G diet for 5 weeks. Dietary C3G significantly reduced blood glucose concentration and enhanced insulin sensitivity. The adiponectin and its receptors expression were not responsible for this amelioration. C3G significantly upregulated the glucose transporter 4 (Glut4) and downregulated RBP4 in the white adipose tissue, which is accompanied by downregulation of the inflammatory adipocytokines (monocyte chemoattractant protein-1 and tumor necrosis factor-α) in the white adipose tissue of the C3G group. These findings indicate that C3G has significant potency in an anti-diabetic effect through the regulation of Glut4-RBP4 system and the related inflammatory adipocytokines.

Keywords: Abbreviations; AMPK; AMP-activated protein kinase; BAT; brown adipose tissue; CCR2; CC chemokine receptor2; C3G; cyanidin 3-glucoside; Cy; cyanidin; G6Pase; glucose-6-phasphatase; Glut4; glucose transporter 4; MCP-1; monocyte chemoattractant protein-1; PPAR; peroxisome proliferator-activated receptor; RBP4; retinol binding protein 4; ROS; reactive oxygen species; TZD; thiazolidinediones; TTBS; Tris–HCl-buffered saline containing 0.05% Tween 20; WAT; white adipose tissuesAnthocyanin; Cyanidin 3-glucoside; Diabetes; Adipocyte; Glucose transporter; Retinol binding protein 4

A₁ receptor deficiency causes increased insulin and glucagon secretion in mice by Stina M. Johansson; Albert Salehi; Marie E. Sandström; Håkan Westerblad; Ingmar Lundquist; Per-Ola Carlsson; Bertil B. Fredholm; Abram Katz (pp. 1628-1635).

Adenosine influences metabolism and the adenosine receptor antagonist caffeine decreases the risk of type 2 diabetes. In this study the metabolic role of one adenosine receptor subtype, the adenosine A₁R, was evaluated in mice lacking this receptor [A₁R (−/−)]. The HbA1c levels and body weight were not significantly different between wild type [A₁R (+/+)] and A₁R (−/−) mice (3–4 months) fed normal lab chow. At rest, plasma levels of glucose, insulin and glucagon were similar in both genotypes. Following glucose injection, glucose tolerance was not appreciably altered in A₁R (−/−) mice. Glucose injection induced sustained increases in plasma insulin and glucagon levels in A₁R (−/−) mice, whereas A₁R (+/+) control mice reacted with the expected transient increase in insulin and decrease in glucagon levels. Pancreas perfusion experiments showed that A₁R (−/−) mice had a slightly higher basal insulin secretion than A₁R (+/+) mice. The first phase insulin secretion (initiated with 16.7mM glucose) was of the same magnitude in both genotypes, but the second phase was significantly enhanced in the A₁R (−/−) pancreata compared with A₁R (+/+). Insulin- and contraction-mediated glucose uptake in skeletal muscle were not significantly different between in A₁R (−/−) and A₁R (+/+) mice. All adenosine receptors were expressed at mRNA level in skeletal muscle in A₁R (+/+) mice and the mRNA A_2AR, A_2BR and A₃R levels were similar in A₁R (−/−) and A₁R (+/+) mice. In conclusion, the A₁R minimally affects muscle glucose uptake, but is important in regulating pancreatic islet function.

Keywords: Adenosine; Metabolism; Islet hormone secretion; Insulin sensitivity; Glucose uptake; A; ₁; receptor

Requirement for protein kinase R in interleukin-1α-stimulated effects in cartilage by Christine L. Tam; Maria Hofbauer; Christine A. Towle (pp. 1636-1641).

Interleukin-1 (IL-1) has pleiotropic effects in cartilage. The interferon-induced, double stranded RNA-activated protein kinase PKR that phosphorylates eukaryotic initiation factor 2 (eIF2) α has been implicated in cytokine effects in chondrocytes. A compound was recently identified that potently suppresses PKR autophosphorylation (IC50 approximately 200ηM) and partially restores PKR-inhibited translation in a cell-free system with significant effect in the nanomolar range. The objectives of this study were to exploit this potent PKR inhibitor to assess whether PKR kinase activity is required for catabolic and proinflammatory effects of IL-1α in cartilage and to determine whether IL-1α causes an increase in eIF2α phosphorylation that is antagonized by the PKR inhibitor. Cartilage explants were incubated with the PKR inhibitor and IL-1α. Culture media were assessed for sulfated glycosaminoglycan as an indicator of proteoglycan degradation and for prostaglandin E₂. Cartilage extracts were analyzed by Western blot for cyclooxygenase-2 and phosphorylated signaling molecules. Nanomolar concentrations of the PKR inhibitor suppressed proteoglycan degradation and cyclooxygenase-2 accumulation in IL-1α-activated cartilage. The PKR inhibitor stimulated or inhibited PGE₂ production with a biphasic dose response relationship. IL-1α increased the phosphorylation of both PKR and eIF2α, and nanomolar concentrations of PKR inhibitor suppressed the IL-1α-induced changes in phosphorylation. The results strongly support PKR involvement in pathways activated by IL-1α in chondrocytes.

Keywords: Cartilage; Interleukin-1; Protein kinase R; Degradation; Cyclooxygenase-2; Eukaryotic initiation factor 2

Repression of matrix metalloproteinase gene expression by ginsenoside Rh2 in human astroglioma cells by So-Young Kim; Dong-Hyun Kim; Sang-Jun Han; Jin-Won Hyun; Hee-Sun Kim (pp. 1642-1651).

Matrix metalloproteinases (MMPs) play an important role in glioma infiltration, facilitating cell migration and tumor invasion through their ability to degrade the extracellular matrix. Therefore, the inhibition of MMPs has been suggested to be a promising therapeutic strategy for brain tumors. This study examined the effect of ginsenoside Rh2 on the expression of MMPs in human astroglioma cells. Rh2 inhibited the PMA-induced mRNA expression of MMP-1, -3, -9, and -14, suggesting that Rh2 has a broad-spectrum inhibitory effect on MMPs. The molecular mechanism underlying MMP-9 inhibition was further investigated because MMP-9 plays a major role in the invasiveness of glioma. It was found that Rh2 inhibited the secretion and protein expression of MMP-9 induced by PMA in human astroglioma cells. The Rh2-mediated inhibition of MMP-9 gene expression appears to occur through NF-κB and AP-1 because their DNA binding and transcriptional activities were suppressed by the agent. Furthermore, Rh2 significantly repressed the PMA-mediated activation of p38 MAPK, ERK and JNK, which are upstream modulators of NF-κB and AP-1. Finally, Rh2 inhibited the in vitro invasiveness of glioma cells, which might be attributed to the broad-spectrum inhibition of MMPs by Rh2. Overall, the strong inhibition of MMP expression by Rh2 might provide a potential therapeutic modality for brain tumors.

Keywords: Abbreviations; MMP; matrix metalloproteinase; ECM; extracellular matrix; PMA; phorbol myristate acetate; MAPK; mitogen-activated protein kinase; ERK; extracellular signal-regulated kinase; JNK; c-Jun N-terminal kinase; NF-κB; nuclear factor-κB; AP; activator protein; EMSA; electrophoretic mobility shift assayRh2; Glioma invasion; MMP; NF-κB; AP-1; MAP kinases

Co-expression of neuropeptide Y Y1 and Y5 receptors results in heterodimerization and altered functional properties by Donald R. Gehlert; Douglas A. Schober; Michelle Morin; Magnus M. Berglund (pp. 1652-1664).

Centrally administered neuropeptide Y (NPY) produces anxiolytic and orexigenic effects by interacting with Y1 and Y5 receptors that are colocalized in many brain regions. Therefore, we tested the hypothesis that co-expression of Y1 and Y5 receptors results in heterodimerization, altered pharmacological properties and altered desensitization. To accomplish this, the carboxyl-termini of Y1 and Y5 receptors were fused with Renilla luciferase and green flourescent protein and the proximity of the tagged receptors assessed using bioluminescent resonance energy transfer. Under basal conditions, cotransfection of tagged Y1 receptor and Y5 produced a substantial dimerization signal that was unaffected by the endogenous, nonselective agonists, NPY and peptide YY (PYY). Selective Y5 agonists produced an increase in the dimerization signal while Y5 antagonists also produced a slight but significant increase. In the absence of agonists, selective antagonists decreased dimerization. In functional studies, Y5 agonists produced a greater inhibition of adenylyl cyclase activity in Y1/Y5 cells than cells expressing Y5 alone while NPY and PYY exhibited no difference. With PYY stimulation, the Y1 antagonist became inactive and the Y5 antagonist exhibited uncompetitive kinetics in the Y1/Y5 cell line. In confocal microscopy studies, Y1/Y5 co-expression resulted in increased Y5 signaling following PYY stimulation. Addition of both Y1 and Y5 receptor antagonists was required to significantly decrease PYY-induced internalization.Therefore, Y1/Y5 co-expression results in heterodimerization, altered agonist and antagonist responses and reduced internalization rate. These results may account for the complex pharmacology observed when assessing the responses to NPY and analogs in vivo.

Keywords: Abbreviations; ALPHA; amplified luminescent proximity homogenous assay; AV12; Syrian hamster salivary cell line; BIBP3226; R; -; N; ²; -(diphenylacetyl)-; N; -(4-hydroxyphenyl)-methyl argininamide; BRET; bioluminescence resonance energy transfer; CGP71683A; (; trans; -naphtalene-1-sulphonic acid [4-[(4-amino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl]-amide hydrochloride); GFP; green fluorescent protein; GPCR; G-protein-coupled receptor; h; human; HEK; human embryonic kidney; LY366258; 1-[3-[1-[2-(4-iodophenyl)ethyl]piperidin-4-yl]propyl]-2-[(phenoxy)methyl]-4-[3-(1-piperidinyl)propoxy]-1H-benzimiazole; Novartis-1; (; trans; -2-nitrobenzene-2-sulfonic acid (4-(2-naphthylmethylamino)methyl) cyclohexyl methyl)amide; PP; pancreatic polypeptide; PYY; peptide YY; RLUC; Renilla; luciferase; rh; rhesus monkeyGPCR heterodimers; Feeding; Anxiety; GPCR internalization; Desensitization; Neuropeptide Y

Regulation of hepatic bile acid transporters Ntcp and Bsep expression by Xingguo Cheng; David Buckley; Curtis D. Klaassen (pp. 1665-1676).

Sodium-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) are two key transporters for hepatic bile acid uptake and excretion. Alterations in Ntcp and Bsep expression have been reported in pathophysiological conditions. In the present study, the effects of age, gender, and various chemicals on the regulation of these two transporters were characterized in mice. Ntcp and Bsep mRNA levels in mouse liver were low in the fetus, but increased to its highest expression at parturition. After birth, mouse Ntcp and Bsep mRNA decreased by more than 50%, and then gradually increased to adult levels by day 30. Expression of mouse Ntcp mRNA and protein exhibit higher levels in female than male livers. No gender difference exists in BSEP/Bsep expression in human and mouse livers. Hormone replacements conducted in gonadectomized, hypophysectomized, and lit/lit mice indicate that female-predominant Ntcp expression in mouse liver is due to the inhibitory effect of male-pattern GH secretion, but not sex hormones. Ntcp and Bsep expression are in general resistant to induction by a large battery of microsomal enzyme inducers. Administration of cholestyramine increased Ntcp, whereas chenodeoxycholic acid (CDCA) increased Bsep mRNA expression. In conclusion, mouse Ntcp and Bsep are regulated by age, gender, cholestyramine, and bile acid, but resistant to induction by most microsomal enzyme inducers.

Keywords: Abbreviations; bDNA; branched DNA signal amplification assay; Bsep; bile salt export pump; DHT; 5α-dihydrotestosterone; E2; 17β-estadiol; GHRH; growth hormone releasing hormone; GNX; gonadectomy; HX; hypophysectomy; Ntcp; sodium-taurocholate cotransporting polypeptideNtcp; Bsep; Gender; Ontogeny; Microsomal enzyme inducer; Enterohepatic circulation of bile acids

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Biochemical Pharmacology (v.74, #11)