Abstract:
:S-Adenosylmethionine (SAMe) and its metabolite 5'-methylthioadenosine (MTA) inhibit mitogen-induced proliferative response in liver and colon cancer cells. SAMe and MTA are also proapoptotic in liver cancer cells by selectively inducing Bcl-x(S) expression. The aims of this work were to assess whether these agents are proapoptotic in colon cancer cells, and if so, to elucidate the molecular mechanisms. We found that both SAMe and MTA are proapoptotic in HT-29 and RKO cells in a dose- and time-dependent manner. Gene microarray uncovered down-regulation of cellular FLICE inhibitory protein (cFLIP). SAMe and MTA treatment led to a decrease in the mRNA and protein levels of both the long and short cFLIP isoforms. This required de novo RNA synthesis and was associated with activation of procaspase-8, Bid cleavage, and release of cytochrome c from the mitochondria. Inhibiting caspase 8 activity or overexpression of cFLIP protected against apoptosis, whereas supplementing with polyamines did not. SAMe and MTA treatment sensitized RKO cells to tumor necrosis factor alpha-related apoptosis-inducing ligand-induced apoptosis. Although SAMe and MTA are proapoptotic in colon cancer cells, they have no toxic effects in NCM460 cells, a normal colon epithelial cell line. In contrast to liver cancer cells, SAMe and MTA had no effect on Bcl-x(S) expression in colon cancer cells. In conclusion, SAMe and MTA are proapoptotic in colon cancer cells but not normal colon epithelial cells. One molecular mechanism identified is the inhibition of cFLIP expression. SAMe and MTA may be attractive agents in the chemoprevention and treatment of colon cancer.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Li TW,Zhang Q,Oh P,Xia M,Chen H,Bemanian S,Lastra N,Circ M,Moyer MP,Mato JM,Aw TY,Lu SCdoi
10.1124/mol.108.054411subject
Has Abstractpub_date
2009-07-01 00:00:00pages
192-200issue
1eissn
0026-895Xissn
1521-0111pii
mol.108.054411journal_volume
76pub_type
杂志文章abstract::15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a cyclopentenonic prostaglandin endowed with powerful anti-inflammatory activities, as shown in animal models of inflammatory/autoimmune diseases, where pharmacological administration of this prostanoid can ameliorate inflammation and local tissue damage via act...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.038042
更新日期:2007-11-01 00:00:00
abstract::Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common malignancies worldwide, with low 5-year survival rates. Current strategies that block epidermal growth factor receptor (EGFR) have limited effects when administered as single agents. Targeting EGFR via intratumoral administration of phospho...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.041160
更新日期:2008-03-01 00:00:00
abstract::Aflatrem, a mycotoxin from Aspergillus flavus, potentiates the gamma-aminobutyric acid (GABA)-induced chloride current. This positive allosteric regulatory action of aflatrem was quantitatively studied on the GABAA receptor channel expressed in Xenopus oocytes after injection with chick brain mRNA under voltage-clamp ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-03-01 00:00:00
abstract::Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 (IL-24), a member of the IL-10 cytokine gene family, preferentially induces cell death in neoplastic epithelial cells types while sparing their normal counterparts. The effects of mda-7/IL-24 in acute myeloid leukemia (AML) cells have not been extensive...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.068007
更新日期:2010-12-01 00:00:00
abstract::Previous studies have shown that neural stimulation of brown adipose tissue (BAT) reorganizes the expression and activity of signaling proteins in the beta-adrenergic adenylyl cyclase pathway. Cold stress increases neural stimulation of BAT and increases alpha1-adrenergic receptor number; however, the alpha1 receptor ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.4.644
更新日期:1997-04-01 00:00:00
abstract::Chronic morphine treatment has been shown to produce constitutive activation of mu-opioid receptors, and this transition might contribute to the development of tolerance and dependence. The apparent ability of chronic morphine to increase the spontaneous, agonist-independent activation of mu-opioid receptors may be un...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.60.1.53
更新日期:2001-07-01 00:00:00
abstract::Avermectins are a family of potent broad-spectrum anthelmintic compounds, which bind with high affinity to membranes isolated from the free-living nematode Caenorhabditis elegans. Binding of avermectins is thought to modulate chloride channel activity, but the exact mechanism for anthelmintic activity remains to be de...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-09-01 00:00:00
abstract::Studies investigating the effects of beta-naphthoflavone (beta NF) on insulin receptor binding and its intrinsic protein kinase activity in rat liver and placenta were performed. Membranes were prepared from maternal liver and placenta on gestation day 11 and used for [125I]insulin radioreceptor assay. Scatchard analy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-03-01 00:00:00
abstract::The congenital long QT syndrome is an inherited disorder characterized by a delay in cardiac repolarization, leading to lethal cardiac arrhythmias such as torsade de pointes. One form of this disease involves mutations in the voltage-dependent cardiac Na(+) channel, which includes an in-frame deletion of three amino a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:2000-02-01 00:00:00
abstract::We synthesized a novel platinum drug, cis-[PtCl(NH3)2(N7-ACV)]+, in which ACV is the antiviral drug acyclovir [a deoxyriboguanosine analogue, 9-(2-hydroxyethoxymethyl)guanine]. This new compound exhibits antiviral efficacy in vitro and exhibits an antitumor activity profile different from that of cisplatin [Metal-Base...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1998-05-01 00:00:00
abstract::G protein activation by different mu-selective opioid agonists was examined in rat thalamus, SK-N-SH cells, and mu-opioid receptor-transfected mMOR-CHO cells using agonist-stimulated guanosine-5'-O-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding to membranes in the presence of excess GDP. [D-Ala2, N-MePhe4, Gly5-...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.1.87
更新日期:1997-01-01 00:00:00
abstract::Although the thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well established agents for the treatment of leukemia, controversies remain regarding their main mode of action. Previous evidence has suggested that although 6-TG exerts a cytotoxic effect through incorporation of 6-thioguanine nucleot...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.1.102
更新日期:2002-07-01 00:00:00
abstract::The molecular determinants of high-affinity human ether-a-go-go-related gene (HERG) potassium channel blockade by methanesulfonanilides include two aromatic residues (Phe656 and Tyr652) on the inner helices (S6) and residues on the pore helices that face into the inner cavity, but determinants for lower-affinity HERG ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.001743
更新日期:2004-11-01 00:00:00
abstract::All five (m1-m5) muscarinic receptors are sensitive to allosteric regulation, but gallamine is considerably more potent in slowing the dissociation of N-[3H]methylscopolamine (NMS) from the m2 subtype than from the m3 or m5 subtypes. To study the structural basis for the preference of gallamine for the m2 subtype, we ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-09-01 00:00:00
abstract::Thromboxane A2 stimulation of smooth muscle cells contributes to the development of vascular lesions after percutaneous transluminal coronary angioplasty. In view of this, we examined the signaling pathways stimulated by a thromboxane receptor agonist, U-46619, in cultures of rat aortic smooth muscle cells. Treatment ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-11-01 00:00:00
abstract::The growth of Plasmodium falciparum, a human malaria parasite, is sensitive to inhibition by chelators of several types. The alkylthiocarbamates and 8-hydroxyquinoline at pharmacologic doses selectively inhibit glycolysis within 6 hr in parasitized erythrocytes. The mechanism attributed to these agents is through the ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-10-01 00:00:00
abstract::The aryl hydrocarbon receptor (AHR) binds planar aromatic compounds and up-regulates the transcription of a battery of xenobiotic-metabolizing enzymes. To identify proteins involved in the biosynthesis of endogenous AHR ligands, we screened extracts of various mouse tissues for AHR signaling activity. We found heart e...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.3.550
更新日期:2003-09-01 00:00:00
abstract::In cervical cancer, the p53 and retinoblastoma (pRb) tumor suppressor pathways are disrupted by the human papilloma virus (HPV) E6 and E7 oncoproteins, because E6 targets p53 and E7 targets pRb for rapid proteasome-mediated degradation. We have investigated whether E6 suppression with small interfering RNA (siRNA) res...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.076539
更新日期:2012-05-01 00:00:00
abstract::Leukotriene B4 (LTB4) induced rapid breakdown of prelabeled inositol phospholipids in rat peritoneal polymorphonuclear leukocytes (PMNs). Formation of [3H]inositol triphosphate ([3H]IP3) was rapid, with a peak of 250-300% of the control level, after 5-15 sec of exposure to LTB4. Accumulation of [3H]inositol bisphospha...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-09-01 00:00:00
abstract::A site-directed alkylating agent was used to inactivate one or more types of opioid receptor in two bioassay preparations in the presence of type-selective ligands as protectors of other opioid receptor types. Since the pharmacological potency of an agonist is decreased when the receptor type through which it acts has...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-05-01 00:00:00
abstract::Organic anion transporter-1 (OAT1) mediates the body disposition of a diverse array of clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti-inflammatories. Therefore, understanding the regulation of OAT1 has profound clinical significance. We previously...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.086769
更新日期:2013-07-01 00:00:00
abstract::Human serum butyrylcholinesterase (Hu BChE) is a promising therapeutic against the toxicity of chemical warfare nerve agents. We have showed previously that recombinant (r) Hu BChE can be expressed at very high levels, 400 to 600 U/ml in mouse blood, by delivering the Hu BChE gene using adenovirus (Ad). Here, we repor...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.055665
更新日期:2009-09-01 00:00:00
abstract::The metabotropic glutamate receptor subtype 5 (mGlu5) activates calcium mobilization via binding of glutamate, the major excitatory neurotransmitter in the central nervous system. Allosteric modulation of the receptor has recently emerged as a promising alternative method of regulation to traditional regulation throug...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.016139
更新日期:2005-12-01 00:00:00
abstract::Post-transcriptional protein synthesis by GH3 cloned pituitary cells, which secrete prolactin and growth hormone, is dependent on Ca2+. The effects of antagonists of prolactin secretion were examined on overall protein synthesis in GH3 cells as a function of cellular Ca2+ depletion and restoration at varying concentra...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-04-01 00:00:00
abstract::Glutathione-S-transferase-catalyzed conjugation of glutathione (GSH) to aflatoxin B1-8,9-epoxide plays an important role in preventing binding of this ultimate carcinogen to target macromolecules. Once formed, the aflatoxin B1-epoxide-GSH conjugates are actively extruded from the cell by an unidentified ATP-dependent ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.6.1034
更新日期:1997-06-01 00:00:00
abstract::Exposure to hepatitis C virus (HCV) can lead to the development of cirrhosis and hepatocellular carcinoma. To examine the effects of long-term HCV infection on hepatic cytochrome P450 1A1 (CYP1A1) expression and function, we used a human hepatoma cell line expressing the HCV subgenomic replicon (Huh.8) to evaluate CYP...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.024125
更新日期:2006-09-01 00:00:00
abstract::2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was found to activate protein kinases under cell- and nucleus-free conditions in isolated C57 mouse liver cytosol (100,000 x g supernatant). This action of TCDD was found to be aryl hydrocarbon receptor (AHR) dependent, concentration dependent, and inhibited by genistein, a t...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.4.667
更新日期:1997-10-01 00:00:00
abstract::We have investigated various nitric oxide (NO) synthase inhibitors for their affinity and selectivity toward the three human isoenzymes in radioligand binding experiments. Therefore, we developed the new radioligand [(3)H]2-amino-4-picoline to measure binding of these compounds to the three human NO synthase (NOS) iso...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:2000-11-01 00:00:00
abstract::Recent clinical studies reveal that selective agonists of group II metabotropic glutamate (mGlu) receptors have robust efficacy in treating positive and negative symptoms in patients with schizophrenia. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs and reduce the ability o...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.035170
更新日期:2007-08-01 00:00:00
abstract::Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that are involved in lipid metabolism, differentiation, proliferation, cell death, and inflammation. Three subtypes have been identified: PPAR-alpha, -delta, and -gamma. We have previously shown presence of PPAR-gamma mRNA in the amn...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.6.1586
更新日期:2003-12-01 00:00:00