Check out our New Publishers' Select for Free Articles

Biochemical Pharmacology (v.83, #3)

Editorial Board (pp. iii).

Emerging insights into the molecular biology of brain metastases by Guo Chen; Michael A. Davies (pp. 305-314).

One of the foremost challenges in oncology is developing improved therapies for preventing and treating metastases to the brain. Recent research in this area is bringing about a shift in the understanding of brain metastases. Previously, the occurrence and poor outcomes associated with brain metastases have been largely attributed to the exclusion of anticancer drugs from the brain by the blood–brain barrier (BBB). However, studies in multiple tumor types have also demonstrated that brain metastases have significant molecular differences from primary tumors and extracranial metastases. These molecular differences may not only promote the formation of brain metastases, but they may also contribute to these tumors’ poor responsiveness to therapies. Such changes may be intrinsic to the cancer cells or driven by unique interactions with the brain microenvironment. An improved understanding of the molecular characteristics of brain metastases that contribute to their aggressive behaviors will facilitate the development of rational, more effective treatments for these tumors.

Keywords: Abbreviations; ADAM9; a disintegrin and metalloprotease 9; BBB; blood–brain barrier; BCL2-L1; B-cell leukemia 2-like 1; BIRC5; baculoviral IAP repeat-containing 5; cDNA; coding DNA; CNS; central nervous system; ECM; extracellular matrix; EGFR; epidermal growth factor receptor; ER; estrogen receptor; ERBB; avian erythroblastic leukemia viral oncogene homolog; FAK; focal adhesion kinase; FISH; fluorescence; in situ; hybridization; GSTA5; glutathione S-transferase alpha 5; HBEGF; heparin-binding EGF-like growth factor; HER; human epithelial growth factor receptor; HGF; hepatocyte growth factor; HK2; hexokiase 2; HSPG; heparan sulfate proteoglycans; IHC; immunohistochemistry; IL; interleukin; JAG2; Jagged 2; LEF1; lymphoid enhancer-binding factor 1; LMD; leptomeningeal disease; MAPK; mitogen-activated protein kinase; MCL1; myeloid cell leukemia-1; MEK; MAPK/ERK kinase; mTOR; mammalian target of rapamycin; pAKT; phosphorylated AKT; PDGF; platelet-derived growth factor; PDGFR; platelet-derived growth factor receptor; PET; positron emission tomography; PI3K; phosphoinositol-3-kinase; PTEN; phosphatase and tensin homolog; RAS; rat sarcoma viral oncogene homolog; ROR2; receptor tyrosine kinase-like orphan receptor 2; SCID; severe combined immunodeficient; siRNA; small interfering RNA; SOCS1; suppressor of cytokine signaling 1; SYK; spleen tyrosine kinase; TCF; T-cell factor; TGF; transforming growth factor; VEGF; vascular endothelial growth factor; VEGFR; vascular endothelial growth factor receptor; WBRT; whole-brain radiation therapy; WNT; wingless-typeBrain metastasis; Blood–brain barrier; Angiogenesis; Targeted therapy; Animal models; Microenvironment

Subchondral bone as a key target for osteoarthritis treatment by Santos Castañeda; Jorge A. Roman-Blas; Raquel Largo; Gabriel Herrero-Beaumont (pp. 315-323).

Osteoarthritis treatment should contemplate the improvement of subchondral bone quality. This therapeutic approach must be individualized in each patient depending on the BMD status and the physiopathological subgroup of osteoarthitis (OA). BMD: bone mineral density; SB: subchondral bone.Osteoarthritis (OA), the most common form of arthritis, is a debilitating and progressive disease that has become a major cause of disability and impaired quality of life in the elderly. OA is considered an organ disease that affects the whole joint, where the subchondral bone (SB) plays a crucial role. Regardless of whether SB alterations precede cartilage damage or appear during the evolution of the disease, SB is currently recognised as a key target in OA treatment. In fact, bone abnormalities, especially increased bone turnover, have been detected in the early evolution of some forms of OA. Systemic osteoporosis (OP) and OA share a paradoxical relationship in which both high and low bone mass conditions may result in induction and/or OA progression. Recent findings suggest that some drugs may be useful in treating both processes simultaneously, at least in a subgroup of patients with OA and OP. This review focuses on the role of SB in OA pathogenesis, describing relevant underlying mechanisms involved in the process and examining the potential activity as disease-modifying anti-osteoarthritic drugs (DMOADs) of certain SB-targeting agents currently under study.

Keywords: Subchondral bone; Osteoarthritis; Pathogenesis; Antiresorptives; New therapies

Differential expression and roles of volume-activated chloride channels in control of growth of normal and cancerous nasopharyngeal epithelial cells by Linyan Zhu; Haifeng Yang; Wanhong Zuo; Linjie Yang; Haifeng Zhang; Wencai Ye; Jianwen Mao; Lixin Chen; Liwei Wang (pp. 324-334).

We have previously shown that chloride channel activities were cell cycle-dependent and were involved in cell proliferation in nasopharyngeal carcinoma cells. In this study, the expression and roles of volume-activated chloride channels in cell growth were investigated in the poorly-differentiated human nasopharyngeal carcinoma cell (CNE-2Z) and its counterpart, the normal human nasopharyngeal epithelial cell (NP69-SV40T). Consistent with growth ability, the background chloride currents recorded under isotonic condition, the volume-activated chloride currents induced by 47% hypotonic challenges and the hyponinicity-induced regulatory volume decrease (RVD) were much larger in CNE-2Z cells than in NP69-SV40T cells, suggesting the up-regulation of expression of volume-activated chloride channels in cancerous cells. This was proved by the up-regulation of ClC-3 proteins, a candidate of volume-activated chloride channels, in the cancerous cells. Functional inhibition of chloride channel activities by the chloride channel blockers, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and tamoxifen, and knock-down of ClC-3 expression by specific ClC-3 siRNA attenuated the background currents, suppressed the activation of volume-activated chloride currents, decreased the hyponinicity-induced RVD and inhibited cell growth in the cancerous and normal cells. However, the sensitivities of the cancerous cells were much higher than that of the normal cells. Our data suggest that volume-activated chloride channels play a more important role in control cell proliferation in the cancerous cells than in the normal cells; the growth of cancerous cells is more dependent on the activities of volume-activated chloride channels than that of the normal cells. ClC-3 protein may be considered as a potential tumor marker and therapeutic target for human nasopharyngeal carcinoma

Keywords: Cancer; Chloride channels; Cell proliferation; ClC-3; Nasopharyngeal carcinoma

CCL2 increases MMP-9 expression and cell motility in human chondrosarcoma cells via the Ras/Raf/MEK/ERK/NF-κB signaling pathway by Chih-Hsin Tang; Chia-Chun Tsai (pp. 335-344).

Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family that is associated with the disease status and outcomes of cancers. However, the effect of CCL2 on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that CCL2 increased the migration and expression of matrix metalloproteinase (MMP)-9 in human chondrosarcoma cells. CCL2-mediated migration and MMP-9 up-regulation were attenuated by CCR2, Ras, Raf-1, and MEK inhibitor. Activation of the Ras, Raf-1, MEK, ERK, and NF-κB signaling pathway after CCL2 treatment was demonstrated, and CCL2-induced expression of MMP-9 and migration activity were inhibited by the specific inhibitor, and mutant of Ras, Raf-1, MEK, ERK, and NF-κB cascades. Taken together, our results indicated that CCL2 enhances the migration of chondrosarcoma cells by increasing MMP-9 expression through the CCR2 receptor, Ras, Raf-1, MEK, ERK, and NF-κB signal transduction pathway.

Keywords: CCL2; Migration; Chondrosarcoma; Ras; Raf-1

Corrector-mediated rescue of misprocessed CFTR mutants can be reduced by the P-glycoprotein drug pump by Tip W. Loo; M. Claire Bartlett; Li Shi; David M. Clarke (pp. 345-354).

Higher concentration of corrector is required for rescue of CFTR in the presence of P-glycoprotein.The most common cause of cystic fibrosis is deletion of Phe508 in the first nucleotide-binding domain (NBD) of the CFTR chloride channel, which inhibits protein folding. ΔF508 CFTR can be rescued by indirect approaches such as low temperature but the protein is unstable. Here, we tested our predictions that (1) other CFTR mutants such V232D and H1085R were more stable at the cell surface than ΔF508 CFTR after low temperature rescue and (2) the advantages of rescue with specific correctors (pharmacological chaperones) are that they may stabilize ΔF508 CFTR and increase the effectiveness of the correctors by bypassing drug pumps such as P-glycoprotein (P-gp) (increased bioavailability). It was found that the stability of mutants V232D and H1085R after low-temperature (30°C) rescue was about 10-fold higher than ΔF508 CFTR. We show that the corrector, 4,5,7-trimethyl-N-phenylquinolin-2-amine (5a), could stabilize ΔF508 CFTR at the cell surface. Unlike most correctors, corrector 5a showed specificity for CFTR as it did not rescue the G268V P-gp processing mutant nor stimulate the ATPase activity of wild-type P-gp. By contrast, corrector KM11060 was a P-gp substrate as it stimulated P-gp ATPase activity and rescued the G268V mutant. Expression of wild-type P-gp reduced the effectiveness of CFTR rescue by corrector KM11060 by about 5-fold. The results underlie the importance of selecting correctors that are specific for CFTR because their efficiency can be reduced by drug pumps such as P-gp.

Keywords: Abbreviations; CFTR; cystic fibrosis transmembrane conductance regulator; TMD1+2; truncated CFTR mutant containing residues 1–388 (TMD1) and residues 847–1196 (TMD2); TMD; transmembrane domain; NBD; nucleotide-binding domain; P-gp; P-glycoproteinCFTR; Cystic fibrosis; Corrector; Protein stability; Pharmacological chaperone; P-glycoprotein

Hsp90 inhibitors sensitise human colon cancer cells to topoisomerase I poisons by depletion of key anti-apoptotic and cell cycle checkpoint proteins by Anne V. McNamara; Monica Barclay; Alastair J.M. Watson; John R. Jenkins (pp. 355-367).

Hsp90 and topoisomerase I are both targets for chemotherapeutic agents. Topoisomerase I poisons are standard clinical treatments, whilst Hsp90 inhibitors are progressing through clinical trials. We have demonstrated that when an Hsp90 inhibitor and topoisomerase I poison are combined they produce a synergistic increase in apoptosis in both p53^+/+ and p53^−/− HCT116 human colon cancer cells. Lack of p53 is associated with an increase in sensitivity to the combination treatment; p53^+/+ cells treated with the topoisomerase I poison topotecan (TPT) arrest at G2, whereas in p53^−/− cells the additional presence of the Hsp90 inhibitor geldanamycin (GA) selectively abrogates the G2M checkpoint. More importantly we report that there is a common underlying p53-independent mechanism behind the observed synergistic combined drug effect. We show that concurrent treatment with GA and TPT is able to reverse TPT induced up-regulation of the anti-apoptotic protein Bcl2 in both p53^+/+ and p53^−/− HCT116 cells. The data suggests that inhibition of Hsp90 mediates down-regulation of Bcl2 following the combination treatment and cause a synergistic increase in apoptosis in both p53^+/+ and p53^−/− HCT116 cells; p53^−/− HCT116 cells are more sensitive to the treatment because they also fail to arrest at G2 in the cell cycle.

Keywords: Topoisomerase I; Hsp90; P53; Irinotecan; Topotecan; 17AAG

Thiadiazolidinones: A new class of alanine racemase inhibitors with antimicrobial activity against methicillin-resistant Staphylococcus aureus by Mihai Ciustea; Sara Mootien; Adriana E. Rosato; Oriana Perez; Pier Cirillo; Kacheong R. Yeung; Michel Ledizet; Michael H. Cynamon; Paul A. Aristoff; Raymond A. Koski; Paul A. Kaplan; Karen G. Anthony (pp. 368-377).

L2-401 (4-[(4-fluorophenyl)methyl]-2-(4-methylphenyl)-1,2,4-thiadiazolidine-3,5-dione). A novel alanine racemase inhibitor.Methicillin-resistant Staphylococcus aureus (MRSA) is a human pathogen and a major cause of hospital-acquired infections. New antibacterial agents that have not been compromised by bacterial resistance are needed to treat MRSA-related infections. We chose the S. aureus cell wall synthesis enzyme, alanine racemase (Alr) as the target for a high-throughput screening effort to obtain novel enzyme inhibitors, which inhibit bacterial growth. Among the ‘hits’ identified was a thiadiazolidinone with chemical properties attractive for lead development. This study evaluated the mode of action, antimicrobial activities, and mammalian cell cytotoxicity of the thiadiazolidinone family in order to assess its potential for development as a therapeutic agent against MRSA. The thiadiazolidones inhibited Alr activity with 50% inhibitory concentrations (IC₅₀) ranging from 0.36 to 6.4μM, and they appear to inhibit the enzyme irreversibly. The series inhibited the growth of S. aureus, including MRSA strains, with minimal inhibitory concentrations (MICs) ranging from 6.25 to 100μg/ml. The antimicrobial activity showed selectivity against Gram-positive bacteria and fungi, but not Gram-negative bacteria. The series inhibited human HeLa cell proliferation. Lead development centering on the thiadiazolidinone series would require additional medicinal chemistry efforts to enhance the antibacterial activity and minimize mammalian cell toxicity.

Keywords: d; -Alanine; Alanine racemase; Peptidoglycan; MRSA

Schisandrin B suppresses TGFβ1 signaling by inhibiting Smad2/3 and MAPK pathways by Eun-Jung Park; Jung Nyeo Chun; Su-Hwa Kim; Chul Young Kim; Hee Ju Lee; Hye Kyung Kim; Jong Kwan Park; Sung Won Lee; Insuk So; Ju-Hong Jeon (pp. 378-384).

TGFβ1 plays a crucial role in the pathogenesis of vascular fibrotic diseases. Schisandra chinensis ( S. chinensis), which is used as an oriental herbal medicine, is effective in the treatment of vascular injuries that cause aberrant TGFβ1 signaling. In this study, we investigated whether S. chinensis extract and its active ingredients inhibit TGFβ1 signaling in A7r5 vascular smooth muscle cells. We found that S. chinensis extract suppressed TGFβ1 signaling via inhibition of Smad2/3 phosphorylation and nuclear translocation. Among the active ingredients of S. chinensis extract, schisandrin B (SchB) most potently inhibited TGFβ1 signaling. SchB inhibited sustained phosphorylation and nuclear translocation of Smad2/3. Moreover, SchB suppressed TGFβ1-induced phosphorylation of p38 and JNK, which contributed to Smad2/3 inactivation. The present study is the first to demonstrate that S. chinensis extract and SchB inhibit TGFβ1 signaling. Our results may help future investigations to understand vascular fibrosis pathogenesis and to develop novel therapeutic strategies for treatment of vascular fibrotic diseases.

Keywords: Schisandra chinensis; Schisandrin B; TGFβ1; Vascular smooth muscle cell; Vascular fibrotic disease

Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression by Hak-Su Kim; Myung-Jin Kim; Eun Ju Kim; Young Yang; Myeong-Sok Lee; Jong-Seok Lim (pp. 385-394).

Berberine is clinically important natural isoquinoline alkaloid that affects various biological functions, such as cell proliferation, migration and survival. The activation of AMP-activated protein kinase (AMPK) regulates tumor cell migration. However, the specific role of AMPK on the metastatic potential of cancer cells remains largely unknown. The present study investigated whether berberine induces AMPK activation and whether this induction directly affects mouse melanoma cell migration, adhesion and invasion. Berberine strongly increased AMPK phosphorylation via reactive oxygen species (ROS) production. 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), a well-known AMPK activator, also inhibited tumor cell adhesion and invasion and reduced the expression of epithelial to mesenchymal transition (EMT)-related genes. Knockdown of AMPKα subunits using siRNAs significantly abated the berberine-induced inhibition of tumor cell invasion. Furthermore, berberine inhibited the metastatic potential of melanoma cells through a decrease in ERK activity and protein levels of cyclooxygenase-2 (COX-2) by a berberine-induced AMPK activation. These data were confirmed using specific MEK inhibitor, PD98059, and a COX-2 inhibitor, celecoxib. Berberine- and AICAR-treated groups demonstrated significantly decreased lung metastases in the pulmonary metastasis model in vivo. Treatment with berberine also decreased the metastatic potential of A375 human melanoma cells. Collectively, our results suggest that berberine-induced AMPK activation inhibits the metastatic potential of tumor cells through a reduction in the activity of the ERK signaling pathway and COX-2 protein levels.

Keywords: AMPK; Berberine; ROS; Metastasis; ERK; COX-2

Heme oxygenase-1 mediates protective effects on inflammatory, catabolic and senescence responses induced by interleukin-1β in osteoarthritic osteoblasts by Victoria Clérigues; Maria Isabel Guillén; Miguel Angel Castejón; Francisco Gomar; Vicente Mirabet; Maria José Alcaraz (pp. 395-405).

Osteoarthritis (OA) is a chronic degenerative joint disease showing altered bone metabolism. Osteoblasts contribute to the regulation of cartilage metabolism and bone remodeling. We have shown previously that induction of heme oxygenase-1 (HO-1) protects OA cartilage against inflammatory and degradative responses. In this study, we investigated the effects of HO-1 induction on OA osteoblast metabolism. HO-1 was induced with cobalt protoporphyrin IX (CoPP) and by transduction with LV-HO-1. In osteoblasts stimulated with interleukin (IL)-1β, CoPP enhanced mineralization, the expression of a number of markers of osteoblast differentiation such as Runx2, bone morphogenetic protein-2, osteocalcin, and collagen 1A1 and 1A2, as well as the ratio osteoprotegerin/receptor activator of nuclear factor-κB ligand. HO-1 induction significantly reduced the expression of matrix metalloproteinase (MMP)-1, MMP-2 and MMP-3, and the production of pro-inflammatory cytokines such as tumor necrosis factor-α and IL-6 whereas IL-10 levels increased. HO-1 also exerted inhibitory effects on prostaglandin (PG)E₂ production which could be dependent on cyclooxygenase-2 and microsomal PGE synthase-1 down-regulation. The activity of senescence-associated β-galactosidase and the expression of the senescence marker caveolin-1 were significantly decreased after HO-1 induction. The inhibition of nuclear factor-κB activation induced by IL-1β in OA osteoblasts may contribute to some HO-1 effects. Our results have shown that HO-1 decreases the production of relevant inflammatory and catabolic mediators that participate in OA pathophysiology thus eliciting protective effects in OA osteoblasts.

Keywords: Osteoblasts; Heme oxygenase-1; Osteoarthritis; Cytokines; Senescence

A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats by Victoria E. Scott; Timothy A. Vortherms; Wende Niforatos; Andrew M. Swensen; Torben Neelands; Ivan Milicic; Patricia N. Banfor; Andrew King; Chengmin Zhong; Gricelda Simler; Cenchen Zhan; Natalie Bratcher; Janel M. Boyce-Rustay; Chang Z. Zhu; Pramila Bhatia; George Doherty; Helmut Mack; Andrew O. Stewart; Michael F. Jarvis (pp. 406-418).

Blockade of voltage-gated Ca²⁺ channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²⁺ channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC₅₀=0.8μM and 1.4μM, respectively) and T-type (IC₅₀=4.6μM and 1.2μM, respectively) Ca²⁺ channels in FLIPR based Ca²⁺ flux assays. A-686085 also potently blocked L-type Ca²⁺ channels (EC₅₀=0.6μM), however, A-1048400 was much less active in blocking this channel (EC₅₀=28μM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC₅₀=300–365ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²⁺ currents in rat dorsal root ganglion neurons (IC₅₀=3.0μM and 1.6μM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²⁺ channels coupled with pharmacological selectivity vs. L-type Ca²⁺ channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function.

Keywords: Abbreviations; A-686085; (1-(2-(4-(3,5-dimethoxybenzyl)piperazin-1-yl)ethyl)-3,3-bis(4-fluorophenyl)pyrrolidin-2-one); A-1048400; (1-[2-(4-benzhydryl-piperazin-1-yl)-2-oxo-ethyl]-3,3-diphenyl-piperidin-2-one); MW; molecular weight; FLIPR; fluorometric imaging plate reader; DRG; dorsal root ganglion; HEK; human embryonic kidney; HBSS; hanks balanced salt solution; CCI; chronic constriction injury; SNL; spinal nerve ligation; MAP; mean arterial pressure; Cap-SMH; capsaicin induced secondary mechanical hypersensitivity; PWT; paw withdrawal threshold; MPE; maximum possible effect; CFA; complete Freunds’ adjuvant; MIA; monoiodoacetic acid; PEG400; polyethlyene glycol 400; FBS; fetal bovine serum; i.v; intraveneous; p.o; per os; PE; phenylephrineN-type Ca; ²⁺; channels; T-type Ca; ²⁺; channels; Dorsal root ganglion; Neuropathic pain; Nociceptive pain; A-1048400

RegIIA: An α4/7-conotoxin from the venom of Conus regius that potently blocks α3β4 nAChRs by Aldo Franco; Shiva N. Kompella; Kalyana B. Akondi; Christian Melaun; Norelle L. Daly; Charles W. Luetje; Paul F. Alewood; David J. Craik; David J. Adams; Frank Marí (pp. 419-426).

Neuronal nicotinic acetylcholine receptors (nAChRs) play pivotal roles in the central and peripheral nervous systems. They are implicated in disease states such as Parkinson's disease and schizophrenia, as well as addictive processes for nicotine and other drugs of abuse. Modulation of specific nAChRs is essential to understand their role in the CNS. α-Conotoxins, disulfide-constrained peptides isolated from the venom of cone snails, potently inhibit nAChRs. Their selectivity varies markedly depending upon the specific nAChR subtype/α-conotoxin pair under consideration. Thus, α-conotoxins are excellent probes to evaluate the functional roles of nAChRs subtypes.We isolated an α4/7-conotoxin (RegIIA) from the venom of Conus regius. Its sequence was determined by Edman degradation and confirmed by sequencing the cDNA of the protein precursor. RegIIA was synthesized using solid phase methods and native and synthetic RegIIA were functionally tested using two-electrode voltage clamp recording on nAChRs expressed in Xenopus laevis oocytes. RegIIA is among the most potent antagonist of the α3β4 nAChRs found to date and is also active at α3β2 and α7 nAChRs. The 3D structure of RegIIA reveals the typical folding of most α4/7-conotoxins. Thus, while structurally related to other α4/7 conotoxins, RegIIA has an exquisite balance of shape, charge, and polarity exposed in its structure to potently block the α3β4 nAChRs.

Keywords: Abbreviations; AChBP; acetylcholine-binding protein; CNS; central nervous system; DMSO; dimethyl sulfoxide; DTT; dithiothreitol; EST; expressed sequence tag; GABA; _B; R; γ-aminobutyric acid type B receptor; IAM; iodoacetamide; nAChR; nicotinic acetylcholine receptor; PCR; polymerase chain reaction; RACE; rapid amplification of cDNA ends; SCUBA; self-contained underwater breathing apparatus; SE-HPLC; size exclusion HPLC; SPPS; solid phase peptide synthesis; TFA; trifluoroacetic acid Conus regius; α-Conotoxin; Nicotinic acetylcholine receptor; NMR structure; Nicotine addiction

Dichloroacetic acid up-regulates hepatic glutathione synthesis via the induction of glutamate–cysteine ligase by Angelo Theodoratos; Anneke C. Blackburn; Jean Cappello; Padmaja Tummala; Jane E. Dahlstrom; Philip G. Board (pp. 427-433).

Dichloroacetic acid (DCA) has potential for use in cancer therapy and the treatment of metabolic acidosis. However, DCA can create a deficiency of glutathione transferase Zeta (GSTZ1-1). Gstz1 knockout mice have elevated oxidative stress and low glutathione levels that increases their sensitivity to acetaminophen toxicity. As it is highly likely that patients that are treated with DCA will develop drug induced GSTZ1-1 deficiency we considered they could be at risk of elevated toxicity if they are exposed to other drugs that cause oxidative stress or consume glutathione (GSH). To test this hypothesis we treated mice with DCA and acetaminophen (APAP). Surprisingly, the mice pre-treated with DCA suffered less APAP-mediated hepatotoxicity than untreated mice. This protection is most likely due to an increased capacity for the liver to synthesize GSH, since DCA increased the expression and activity of glutamate–cysteine ligase GCL, the rate-limiting enzyme of GSH synthesis. Other pathways for acetaminophen disposal were unchanged or diminished by DCA. Pre-treatment with DCA may be of use in other settings where the maintenance of protective levels of GSH are required. However, DCA may lower the efficacy of drugs that rely on oxidative stress and the depletion of GSH to enhance their cytotoxicity or of drugs that are detoxified by GSH conjugation. Consequently, as the use of DCA in the clinic is likely to increase, it will be critical to evaluate the interactions of DCA with other drugs to ensure the combinations retain their efficacy and do not cause enhanced toxicity.

Keywords: Acetaminophen toxicity; Dichloroacetic acid; Glutathione; Glutamate–cysteine ligase; Liver; Pathology

Sections

Personal tools

Biochemical Pharmacology (v.83, #3)

Sections

Personal tools

Local resources

Biochemical Pharmacology (v.83, #3)