Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors:A case report and literature analysis

Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.

Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors

In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights derived from current studies.Furthermore,we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments.This framework is essential for identifying those at increased risk of HBVr,enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

Three New Hydroxytetradecenals from Amomum tsao-ko with Protein Tyrosine Phosphatase 1B and Glycogen Phosphorylase Inhibitory Activity

The fruits of Amomum tsao-ko(Cao-Guo)were documented in Chinese Pharmacopoeia for the treatment of abdominal pain,vomiting,and plague.In our previous study,a series of diarylheptanes and flavonoids withα-glucosidase and protein tyrosine phosphatase 1B(PTP1B)inhibitory activity have been reported from the middle-polarity part of A.tsao-ko,whereas the antidiabetic potency of the low-polarity constituents is still unclear.In this study,three new hydroxytetradecenals,(2E,4E,8Z,11Z)-6R-hydroxytetradeca-2,4,8,11-tetraenal(1),(2E,4E,8Z)-6R-hydroxytetradeca-2,4,8-trienal(2)and(2E,4E)-6R-hydroxytetradeca-2,4-dienal(3)were obtained from the volatile oils of A.tsao-ko.The structures of compounds 1–3 were determined using spectroscopic data involving 1D and 2D nuclear magnetic resonance(NMR),high-resolution mass spectra(HRMS),and specific rotation([α]D).Their hypoglycemic activity was evaluated against glycogen phosphorylase(GPa)and PTP1B.Compounds 1 and 2 displayed moderate activity against PTP1B with inhibition rates of 33.8%−50.3%at 100 and 200μM.Moreover,compound 1 exhibited an obvious inhibitory effect on GPa(IC50=31.7μM),whereas compound 2 was inactive.This study demonstrates hydroxytetradecenals as the characteristic components of A.tsao-ko with therapeutic potential in diabetes.

The synergistic regulatory effect of PTP1B and PTK inhibitors on the development of Oedaleus decorus asiaticus Bei-Bienko

Tyrosine phosphorylation is crucial for controlling normal cell growth,survival,intercellular communication,gene transcription,immune responses,and other processes.protein tyrosine phosphatase(PTP)and protein tyrosine kinases(PTK)can achieve this goal by regulating multiple signaling pathways.Oedaleus decorus asiaticus is an important pest that infests the Mongolian Plateau grassland.We aimed to evaluate the survival rate,growth rate,overall performance,and ovarian developmental morphology of the 4th instar nymphs of O.decorus asiaticus while inhibiting the activity of protein tyrosine phosphatase-1B(PTP1B)and PTK.In addition,the expression and protein phosphorylation levels of key genes in the MAPK signaling pathway and antioxidant enzyme activity were assessed.The results showed no significant differences in survival rate,growth rate,or overall performance between PTP1B inhibitor treatment and control.However,after PTK inhibitor treatment,these indexes were significantly lower than those in the control.The ovarian size of female larvae after 15 days of treatment with PTK inhibitors showed significantly slower development,while female larvae treated with PTP1B exhibited faster ovarian growth than the control group.In comparison to controls and nymphs treated with PTK inhibitors,the expression and phosphorylation levels of key genes in the MAPK signaling pathway under PTP1B inhibitor treatments were significantly higher in 4th instar nymphs.However,reactiveoxygen(ROS)species levels and the activities of NADPH oxidase and other antioxidant enzymes were considerably reduced,although they were significantly greater in the PTK inhibitor treatment.The results suggest that PTP1B and PTK feedback inhibition in the mitogen-activated-protein kinases(MAPK)signal transfer can regulate the physiological metabolism of the insect as well as its developmental rate.These findings can facilitate future uses of PTP1B and PTK inhibitors in controlling insect development to help control pest populations.

Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Urinary trypsin inhibitor attenuates hepatic ischemia-reperfusion injury by reducing nuclear factor-kappa B activation

BACKGROUND: Urinary trypsin inhibitor (UTI) inhibits the inflammatory response and protects against ischemia-reperfusion (I/R) injury. The inflammatory response is mediated by nuclear factor-kappa B (NF-kappa B) and its related target genes and products such as vascular endothelial cell adhesion molecule and CXC chemokines. We aimed to assess the roles of those mediators in a UTI-treated mouse model of hepatic I/R injury. METHODS: Treatment group 1 (UTI given 5 minutes prior to liver ischemia), treatment group 2 (UTI given 5 minutes after the anhepatic phase) and a control group were investigated. Blood and liver samples were obtained and compared at 1, 3, 6 and 24 hours after reperfusion. RESULTS: Attenuation of pathological hepatocellular damage was greater in the treatment groups than in the control group (P < 0.05). Compared with the control group, the UTI treatment groups showed significantly lower serum alanine aminotransferase and aspartate aminotransferase levels, decreased myeloperoxidase activity, and reduced NF-kappa B activation. Also downregulated was the expression of tumor necrosis factor-alpha, cytokine-induced neutrophil chemoattractant, and macrophage inflammatory protein-2 at the mRNA level. P-selectin protein and intercellular adhesion molecule-1 protein expression were also downregulated. In addition, the treatment group I showed a better protective effect against I/R injury than the treatment group 2. CONCLUSIONS: UTI reduces NF-kappa B activation and downregulates the expression of its related mediators, followed by the inhibition of neutrophil aggregation and infiltration in hepatic I/R injury. The protective role of UTI is more effective in prevention than in treatment.

Calpain inhIbitorⅠ对烧伤小鼠肝脏NF-κB转录及炎性细胞因子分泌的影响

探讨Calpain inhibitor I(CI-I)对严重烧伤小鼠肝脏IκBa表达,NF-κB转录及炎性细胞因子分泌的影响。将CI-Ⅰ腹腔给药预处理小鼠1 h后背部行20%全身体表面积(TBSA)Ⅲ度烧伤,收集肝组织,检测其IκBa表达,NF-κB转录和血清TNF-a、IL-1B、IL-6分泌水平。与烧伤对照组比较,CI-Ⅰ预处理后肝脏NF-κB转录活性和炎性细胞因子分泌有所降低。提示CI-Ⅰ预处理可有效抑制严重烧伤小鼠肝细胞NF-κB活化和血清炎性细胞因子分泌,从而有利于烧伤后的炎症调节。

I_κB kinase-beta inhibitor attenuates hepatic fibrosis in mice

AIM: To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin-6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κB (NF-κB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeⅠand type Ⅲ collagen proteins and mRNA. RESULTS: A mouse model of liver injury was successfully established, and IMD decreased nuclear transloca-tion of NF-κB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeⅠcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type Ⅲ collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05). CONCLUSION: IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver disease in mice by lowering NF-κB activation, which could become a remedial target for liver fibrosis.

Hepatoprotective effects of cathepsin B inhibitor on acute hepatic failure induced by lipopolysaccharide/D-galactosamine in mice

BACKGROUND:Increasing evidence suggests that the inactivation of cathepsin B attenuates hepatocyte apoptosis and liver damage.This study aimed to investigate the protective effects of a cathepsin B inhibitor(CA-074me) on lipopolysaccharide(LPS)/D-galactosamine(D-GalN)-induced acute hepatic failure(AHF) in mice.METHODS:Mice were intraperitoneally injected with a combination of LPS/D-GalN to induce AHF with or without CA-074me pretreatment.The cumulative survival rates were calculated 48 hours after the induction of AHF.As well as changes in biochemical indicators and liver histology,hepatocyte apoptosis was assessed using a TUNEL method.Serum tumor necrosis factor-α(TNF-α) production,caspase-3,caspase-8,and caspase-9 activity was evaluated.Cytosolic cytochrome c and Bcl-2 expression were measured by Western blotting.RESULTS:The marked elevation in serum aminotransferase activity and prothrombin time found in LPS/D-GalN-treated mice was significantly improved by pretreatment with CA074me.The efficacy of CA-074me was also confirmed by histological analysis and TUNEL assay.The survival rate significantly improved in LPS/D-GalN-induced mice given CA-074me compared with untreated mice.LPS/D-GalNinduced caspase-3 and caspase-9 activation was remarkably suppressed by CA-074me.However,the increased levels of serum TNF-α and elevated caspase-8 activity in AHF mice were not significantly reduced by CA-074me.Moreover,CA074me sharply reduced the increased expression of cytosolic cytochrome c and markedly augmented Bcl-2 expression.CONCLUSION:These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.

Purification and Trypsin Inhibitor Activity of a Sporamin B from Sweet Potato (Ipomoea batatas Lam. 55-2)

Sporamin is a soluble protein in sweet potato, and falls into two distinct homology groups, subfamilies A and B. In this research, a sporamin B was purified and its amino acid sequences, trypsin inhibitor activity （Ti activity） were analyzed. This sporamin B was isolated from sweet potato tubers [Ipomoea batatas （L.） Lam cv. 55-2] through extraction of the water-soluble fraction, dialysis, ultrafiltration and ion-exchange chromatography. Homology determined by polyacrylamide gel electrophoresis showed that mainly one bond appeared in gel after being reduced by SDS （sodium dodecyl sulfate）, or by SDS and 2-mercaptoethanol, or in native situation. By comparing the data of the polypeptide mass Matrix-assisted laser desorption/ionization time-of-flight （MALDI-TOF） mass spectrometry with those of the mass of the theoretical amino acid sequences from NCBI protein database, it was revealed that it was Q40091｜Q40091_IPOBA, sweet potato sporamin B - Ipomoea Batatas （sweet potato） （Batate）. The sequence coverage was 70.6%. N-terminal sequence was SETPV （Ser-Glu-Thr-Pro-Val）. There is a linear relationship between trypsin inhibitor activity （Ti activity） and amounts of this sporamin B （3-18 μg mL-1）. The equation of linear regression was y = 2.5809x ＋ 17.049 （r2 = 0.9966）. There was a curvilinear relationship between Ti activity and amounts of this sporamin B （21-150 μg mL-1）. The equation of curvilinear regression is y = 14.417ln（x） ＋ 23.26 （r2 = 0.9924）. The concentration of sporamin B with Ti activity after heating at 40°C may induce part denature of this sporamin B, and there was no statistic difference after heating at 40, 50, 60°C for 20 min. Heat treatment at more than 90°C leads to a dramatic decrease of trypsin inhibitor efficiency. The results suggested that Q40091｜Q40091_IPOBA was the major sporamin B in sweet potato tubers [Ipomoea Batatas （L.） Lam cv. 55-2], which had strong Ti activity, and was stable to both thermal and DTT （DL-dithiothreitol） relatively.

Testosterone alleviates tumor necrosis factor-alpha-mediated tissue factor pathway inhibitor downregulation via suppression of nuclear factor-kappa B in endothelial cells

We have observed earlier that testosterone at physiological concentrations can stimulate tissue factor pathway inhibitor(TFPI)gene expression through the androgen receptor in endothelial cells.This study further investigated the impact of testosterone on TFPI levels in response to inflammatory cytokine tumor necrosis factor-alpha(TNF-α).Cultured human umbilical vein endothelial cells were incubated in the presence or absence of testosterone or TNF-α.TFPI protein and mRNA levels were assessed by enzyme-linked immunosorbent assay and quantitative real-time reverse transcription polymerase chain reaction.To study the cellular mechanism of testosterone’s action,nuclear factor-kappa B(NF-κB)translocation was confirmed by electrophoretic mobility shift assays.We found that after NF-κB was activated by TNF-α,TFPI protein levels declined significantly by 37.3%compared with controls(P<0.001),and the mRNA levels of TFPI also decreased greatly(P<0.001).A concentration of 30 nmol L-1 testosterone increased the secretion of TFPI compared with the TNF-α-treated group.NF-κB DNA-binding activity was significantly suppressed by testosterone(P<0.05).This suggests that physiological testosterone concentrations may exert their antithrombotic effects on TFPI expression during inflammation by downregulating NF-κB activity.

Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene a4 hydrolase and blocking LTB4 biosynthesis

OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.

2D-QSAR Studies on Anthranilic Acid Derivatives: A Novel Class of Allosteric Inhibitors of Hepatitis C NS5B Polymerase

Quantitative structure activity relationship （QSAR） studies were performed on 45 anthranilic acid derivatives for their potent allosteric inhibition activities of HCV NSSB polymerase. Genetic algorithm based genetic function approximation （GFA） method of variable selection was used to generate the model. Highly statistically significant model with r^2 = 0.966 and r^2cv = 0.951 was obtained when the number of descriptors in the equation was set to 5. High r^2pred value of 0.884 indicates the good predictive power of the best model. Spatial descriptors of radius of gyration （RadOfGration）, molecular volume （Vm）, length of molecule in the z dimension （Shadow-Zlength）, thermodynamic descriptors of the octanol/water partition coefficient （LogP） and molecular refractivity index （MR） showed enormous contributions to HCV NS5B polymerase inhibition. The validation of the model was done by leave-one-out （LOO） test, randomization tests and external test set prediction. The model gives insight on indispensable structural requirements for the activity and can be used to design more potent analogs against HCV NSSB polymerase.

Structural Insight into the Design on Oleanolic Acid Derivatives as Potent Protein Tyrosine Phosphatase 1B Inhibitors

Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.

Preparation of AChE Inhibitors From Jujubogenin

A dammarane derivative dihydrojujubogenin-2-en-1-one, which possesses a skeleton and pharmacophore partially similar to those of Territrem B, a potent AChE inhibitor, was synthesized via three different paths. The anti-AChE activity of this compound and related analogue was measured.

Triterpenoids from Uncaria rhynchophylla and Their PTP1B Inhibitory Activity

Uncaria rhynchophylla(Gouteng)is a famous traditional Chinese medicine used for psychiatric and hypotensive purposes in China.In this study,the ethyl acetate(EtOAc)part of U.rhynchophylla was revealed with protein tyrosine phosphatase 1B(PTP1B)inhibitory activity.Subsequent investigation on the EtOAc part yielded one new triterpenoid,3β-formyloxy-6β,19α-dihydroxyurs-12-en-28-oic acid(1)and four known ones,3β,6β,19α-trihydroxyurs-12-en-28-oic acid(2),2-oxopomolic acid(3),3β,19α-dihydroxy-6-oxo-olean-12-en-28-oic acid(4)and sumaresinolic acid(5).The structure of compound 1 was determined by extensive HRESIMS,IR,1D and 2D NMR spectroscopic analyses.Two ursane-type triterpenoids(2 and 3)showed selective inhibition on PTP1B with IC50 values of 48.2 and 178.7μM.The enzyme kinetic study suggested that compounds 2 and 3 were mixtype inhibitors on PTP1B with Ki values of 15.6 and 132.5μM.This investigation manifests the antidiabetic potency of U.rhynchophylla with triterpenoids as the active constituents.

Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor

Hepatitis B virus(HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy.Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors,which are now widely used in the treatment of patients with chronic myeloid leukemia.Although HBV reactivation induced by imatinib mesylate has been reported,nilotinib-related HBV reactivation has not been reported in the English literature.We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.

A Copper(Ⅱ)Complex Based on N-(4-hydroxybenzyl)-L-serine:Synthesis,Crystal Structure and Inhibitory Activity on PTP1B and TCPTP

A novel copper（II） complex with the reduced Schiff base, [Cu（L）2]·H2O （I, HL = N-（4-hydroxybenzyl）-L-serine）, was prepared in aqueous solution and characterized by elemental analysis, FT-IR, electrospray ionization mass spectrometry and single-crystal X-ray diffraction. Complex I crystallizes in the orthorhombic system, space group P212121, with a = 8.9040（18）, b = 9.1530（18）, c = 24.891（5）A^°, V = 2028.6（7） A^°3, Z = 4, C20H26CuN2O9, Mr = 501.97, Dc = 1.644g·cm^3, μ = 1.135 mm^-1, F（000） = 1044, GOOF = 1.194, the final R = 0.0484 and wR = 0.1420 for 6186 observed reflections （I 〉 2σ（I））. In I, two L^- anions are coordinated to the copper ion in tridentate and bidentate chelating modes, respectively, resulting in the coordinated geometry of copper ion to be a distorted square pyramid. The intermolecular hydrogen bonds between the complexes, complexes and lattice water molecules lead to a 2D supramolecular network. The bioactivity of the complex as a potential PTPs inhibitory agent in vitro was investigated, displaying potent inhibition against PTP1B （IC50, 0.27 μM） and TCPTP （IC50, 0.57 μM） with a moderate selectivity.

Effect of a nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on invasion of human colorectal cancer cell line SL-174T

AIM: To investigate the effect and mechanism of action of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on invasion and metastasis of human colorectal cancer cell line SL-174T.METHODS: Human colorectal cancer cell line SL-174T was cultured and treated separately with four different dosages of L-NAME for 72 h. Nitric oxide (NO) production was measured with Griess reagent. The effect of L-NAME on invasion and migration of SL-174T cells were evaluated by using Transwell chambers attached with polycarbonate filters and reconstituted basement membrane (Matrigel).RT-PCR was performed to determine the mRNA levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor metalloproteinase-2 (TIMP-2).RESULTS: L-NAME could significantly inhibit NO production of SL-174T in a dose-dependent manner. After being treated for 72 h with 0.2, 0.4, 0.8, and 1.0 mmol/L LNAME, respectively, the ability of the L-NAME treated SL174T cells to invade the reconstituted basement membrane decreased significantly (t = 8.056, P＜0.05;t= 14.467, P＜0.01;t= 27.785, P＜0.01;and t= 29.405,P＜0.01, respectively) and the inhibition rates were 10.29%,19.62%, 34.08%, and 42.23%, respectively. Moreover,L-NAME could inhibit migration of SL-174T cells, and the inhibition rates were 20.76%, 24.95%, 39.43%, and 46.85% for L-NAME at 0.2, 0.4, 0.8, and 1.0 mmol/L,respectively (t = 15.116, P＜0.01). In addition, after treatment with L-NAME, expression of MMP-2 mRNA was significantly decreased (t = 71.238, P＜0.01) and that of TIMP-2 mRNA was markedly increased (t = -13.020,P＜O.01).CONCLUSION: L-NAME exerts anti-invasive and antimetastatic effects on SL-174T cell line via downregulating MMP-2 mRNA expression and upregulating TIMP-2 mRNA expression.