Abstract:
:Cell based studies have suggested that the diabetes drug metformin may combine with the anaplastic lymphoma kinase receptor (ALK) inhibitor crizotinib to increase ALK positive lung cancer cell killing and overcome crizotinib resistance. We therefore tested metformin alone and in combination with crizotinib in vivo, by employing a xenograft mouse model of ALK positive lung cancer. We found that 14 days of daily oral metformin (100 mg/kg) alone had a moderate but statistically significant effect on tumour growth suppression, but in combination with crizotinib, produced no greater tumour suppression than crizotinib (25 mg/kg) alone. We also reassessed the effect of metformin on EML4-ALK positive lung cancer (H3122) cell viability. Although metformin alone did have a moderate effect on cell viability (30% suppression) this was only at a clinically irrelevant concentration (5 mM) and there was no additive effect with cytotoxic concentrations of crizotinib. Moreover, metformin did not overcome crizotinib resistance in our resistant cells. Nevertheless, we were able to show that metformin induces a G1-cell cycle arrest and apoptosis alone and in combination with crizotinib. Also, consistent with earlier work, the addition of insulin-like growth factor-1 (IGF-1) to EML4-ALK positive cancer cells reduced cell killing by crizotinib. We therefore hypothesised that the effect of metformin in vivo was not due to direct cytotoxicity on cancer cells, but by modulation of IGF-1 expression. We therefore measured levels of IGF-1 in plasma taken from mice treated with metformin, but found no difference between the drug treatment and control groups. We further hypothesised that the effect of metformin could be due to modulation of thrombospondin 1 (TSP-1), which metformin has been proposed to regulatein vivo, but again we found no difference between the experimental groups. Finally, we investigated the potential for liver and kidney toxicity, as well as CYP3A based interactions, from the combination of metformin with crizotinib.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Bland AR,Shrestha N,Bower RL,Rosengren RJ,Ashton JCdoi
10.1016/j.bcp.2020.114345subject
Has Abstractpub_date
2021-01-01 00:00:00pages
114345eissn
0006-2952issn
1873-2968pii
S0006-2952(20)30581-5journal_volume
183pub_type
杂志文章abstract::The large amount of nitric oxide (NO) produced by inducible NO synthase (iNOS) contributes to cellular injury in inflammatory disease. In the present study, a novel synthetic compound (3E)-4-(2-hydroxyphenyl)but-3-en-2-one (HPB) was found to inhibit lipopolysaccharide (LPS)-induced NO generation, but not through the i...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2005.05.032
更新日期:2005-08-15 00:00:00
abstract::Oligodendrocytes and activated macrophages are involved in the immunopathology of demyelinating disease. In this study, we investigated the in vitro effect of dietary compounds, in particular flavonoids, on oxidative damage in OLN-93 oligodendrocytes and on nitric oxide (NO) production by NR8383 macrophages. Using a c...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2003.10.018
更新日期:2004-03-01 00:00:00
abstract::To elucidate the molecular mechanism by which antioxidants alleviate atherosclerosis, we investigated the effect of crocetin, a naturally occurred carotinoid with potent antioxidant power, on vascular cell adhesion molecule-1 (VCAM-1) expression in atherosclerotic rabbits. Twenty-four male New Zealand White rabbits we...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2005.07.034
更新日期:2005-10-15 00:00:00
abstract::Prodrug activation gene therapy for cancer involves expressing prodrug-activating enzymes in tumour cells, so they can be selectively killed by systemically administered prodrug. For example, Escherichia colinfsB nitroreductase (E.C. 1.6.99.7)(NTR), sensitises cells to the prodrug CB1954 (5-[aziridin-1-yl]-2,4-dinitro...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.07.025
更新日期:2010-01-15 00:00:00
abstract::Tannins are polyphenols commonly found in plant-derived foods. When ingested they can have various harmful effects, but salivary proline-rich proteins (PRPs) may provide protection against dietary tannins. The aim of this study was to investigate whether basic PRPs, a major family of salivary proteins, can prevent int...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2006.02.013
更新日期:2006-05-28 00:00:00
abstract::As theophylline, caffeine and acetaminophen (APAP) are commonly found in combination in prescription and non-prescription drugs, the present study was designed to evaluate changes of hepatic glutathione (GSH) and lipid peroxidation in rats treated concurrently with these widely used drugs. In rats treated with differe...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(94)90173-2
更新日期:1994-02-09 00:00:00
abstract::The effect of varying the fatty acid composition of the lipid components of the diet on the activity of epoxide hydratase in the rat liver and intestinal mucosa has been studied. Feeding a 10% cod liver oil diet (containing 18% C20:5 and 11% C22:6) resulted in a 3-fold increase in epoxide hydratase activity in the liv...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(86)90728-8
更新日期:1986-06-15 00:00:00
abstract::5,10-Dideazatetrahydrofolic acid (DDATHF) reduces de nova purine biosynthesis by inhibiting glycinamide ribonucleotide transformylase. ICI D1964 and CB3717 are folate-based inhibitors of thymidylate synthase (TS). Fluorodeoxyuridine (FdUrd) following metabolism to FdUMP also inhibits TS. In cultured L1210 cells DDATHF...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(94)00458-x
更新日期:1995-03-15 00:00:00
abstract::Transient outward potassium current (Ito) contributes to early repolarization of many mammalian cardiac action potentials, including human, whilst the rapid delayed rectifier K+ current (IKr) contributes to later repolarization. Fast Ito channels can be produced from the Shal family KCNDE gene product Kv4.3s, although...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2018.01.036
更新日期:2018-04-01 00:00:00
abstract::Rat liver cells were separated into parenchymal cells (PC), Kupffer cells (KC) and endothelial cells (EC). The distribution of carboxylesterases (EC 3.1.1.1) between these cell types was investigated by PAGE and chromatogenic substrate staining, and compared with the results for total liver preparation and individual ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(92)90423-g
更新日期:1992-08-18 00:00:00
abstract::Allosteric regulation of [3H]N-methylscopolamine [( 3H]NMS) and [3H]quinuclidinyl benzilate [( 3H]QNB) dissociation from the m1-m5 muscarinic receptor subtypes was examined in transfected CHO-K1 cells. Half-times of dissociation of [3H]NMS from cell membranes (at 23 degrees) ranged from less than 5 min for the m2 subt...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90591-r
更新日期:1991-10-24 00:00:00
abstract::In vitro covalent binding of a chemically reactive metabolite of propranolol to microsomal macromolecules, which is presumed to cause inhibition of its own metabolism in rats, was diminished in liver microsomes from rats pretreated with propranolol. Covalent binding was suppressed by the addition of an antibody agains...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(94)90587-8
更新日期:1994-11-16 00:00:00
abstract::The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by compu...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2017.10.009
更新日期:2017-12-15 00:00:00
abstract::The cytoprotective effect of curcumin, a natural constituent of Curcuma longa, on the cytotoxicity of paracetamol in rat hepatocytes was studied. Paracetamol was selected as a model-toxin, since it is known to be bioactivated by 3-methylcholanthrene inducible cytochromes P450 presumably to N-acetyl-p-benzoquinone imin...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(90)90603-i
更新日期:1990-06-15 00:00:00
abstract::Adherence of Plasmodium falciparum-infected erythrocytes (IE) to the venular endothelium in brain and other organs is characteristic of cerebral malaria, an often fatal complication in infected individuals. It has been shown that cytoadherence may be mediated through interaction of IE with glycoproteins on host target...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90124-n
更新日期:1991-06-15 00:00:00
abstract::Melatonin (MEL) has been proposed as a therapeutic agent for the oral cavity, due to its antioxidant and anti-inflammatory effects since periodontal diseases are aggravated by free radicals, and by disproportionate immunological response to plaque microorganism. In addition, MEL promotes bone formation. This study aim...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2013.10.009
更新日期:2013-12-15 00:00:00
abstract::During the molecular transduction of itch, the stimulation of pruriceptors on sensory fibers leads to the activation or sensitization of ion channels, which results in a consequent depolarization of the neurons. These ion channels mostly belong to the transient receptor potential (TRP) channels, which are involved in ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2020.114310
更新日期:2021-01-01 00:00:00
abstract::The family of natural red pigments, called prodigiosins (PGs), characterised by a common pyrrolylpyrromethene skeleton, are produced by various bacteria. Some members have immunosuppressive properties and apoptotic effects in vitro and they have also displayed antitumour activity in vivo. Understanding the mechanism o...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/s0006-2952(03)00496-9
更新日期:2003-10-15 00:00:00
abstract::The disturbances of the cholesterol synthesis and metabolism described in Alzheimer's disease (AD) may be both a consequence of the neurodegenerative process and a contributor to the pathogenesis. These putative relationships and their underlying mechanisms are not well understood. The aim of this study was to evaluat...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2012.12.007
更新日期:2013-07-01 00:00:00
abstract::EO9 is a novel bioreductive drug which has recently undergone extensive clinical evaluation. Its mechanism of action remains to be clearly defined. Antitumour activity of EO9 has been determined in 2 human colon cancer xenografts (HT-29 and BE) and 2 murine colon adenocarcinomas (MAC 16 and 26) after intratumoural inj...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(97)00265-7
更新日期:1998-02-01 00:00:00
abstract::Cytogenetic lesions often alter kinase signaling in acute myeloid leukemia (AML) and the addition of kinase inhibitors to the treatment arsenal is of interest. We have screened a kinase inhibitor library and performed combination testing to find promising drug-combinations for synergistic killing of AML cells. Cytotox...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2016.08.020
更新日期:2016-10-15 00:00:00
abstract::To investigate the potential interactions between the angiotensin II (Ang II) and insulin signaling systems, regulation of IRS-1 phosphorylation and insulin-induced Akt activation by Ang II were examined in clone 9 (C9) hepatocytes. In these cells, Ang II specifically inhibited activation of insulin-induced Akt Thr(30...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.10.014
更新日期:2010-03-01 00:00:00
abstract::The enhanced nitric oxide (NO) and prostaglandin (PG) generation of activated macrophages is controlled by glucocorticoid-sensitive inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. Negative feedback regulation of iNOS expression by the products of both pathways has been suggested, but...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(96)00737-x
更新日期:1997-02-21 00:00:00
abstract::In assessing the biological effects of exposure to a complex chemical mixture, it is important to determine how the behavior of one compound may be influenced by the presence of other compounds in the mixture. In this study the effect of pre-exposure to an organic extract of diesel exhaust or to selected compounds in ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(86)90581-2
更新日期:1986-07-01 00:00:00
abstract::The experiments were designed to investigate some details of the action of 3-methylcholanthrene (3-MC) on the regulation of transcription. After a single intraperitoneal dose of 3-MC a significant increase in the activities of both nucleolar and nucleoplasmic protein kinases in hepatic cells of young rats was found. T...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90343-4
更新日期:1982-03-15 00:00:00
abstract::Metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone, MTP) is used as an inhibitor of cytochrome P-450 enzymes, particularly those induced by phenobarbital (PB). We examined the effects of MTP on the microsomal dependent mutagenesis of a newly isolated promutagen, 3-(2-chloroethoxy)-1,2-dichloropropene (CP), three S-chlo...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(83)90144-2
更新日期:1983-12-15 00:00:00
abstract::Aldehyde oxidase (AOX) is a cytosolic enzyme responsible for the metabolism of some drugs and drug candidates. AOX catalyzes the oxidative hydroxylation of substrates including several aliphatic and aromatic aldehydes, and nitrogen-containing heterocyclic compounds. AOX is also reported to catalyze the reductive metab...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2017.09.002
更新日期:2017-12-01 00:00:00
abstract::Radioligand binding techniques are commonly used in the characterization of beta-adrenergic receptors on human peripheral leukocytes. Accurate interpretation of receptor binding parameters necessitates appropriate radioligand selection. In addition, cell isolation techniques should have minimal effect on the binding p...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(87)90041-4
更新日期:1987-05-15 00:00:00
abstract::The in vitro and in vivo effects of fluoxetine (and its active metabolite norfluoxetine) on mitochondrial respiration and F0F1-ATPase were studied, respectively, in mitochondria and submitochondrial particles isolated from rat liver. Fluoxetine in vitro inhibited state 3 mitochondrial respiration for alpha-ketoglutara...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(94)90283-6
更新日期:1994-08-03 00:00:00
abstract::The inhibition of renal ornithine decarboxylase (ODC) by aminoglycoside antibiotics was characterized in the postmitochondrial fraction of a kidney homogenate from adult pigmented guinea pigs. Enzymatic activity was defined as the rate of decarboxylation of [14C]ornithine sensitive to a specific ODC inhibitor, alpha-d...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(88)90427-3
更新日期:1988-05-01 00:00:00