ABSTRACT
OBJECTIVES@#To investigate the effect of adriamycin (ADM), idelalisib or ADM and their combination on cell proliferation and intracellular concentration of ADM, and to explore the reversal effect of idelalisib on drug resistance to ADM.@*METHODS@#The K562 and K562/ADM cells were respectively treated with ADM and idelalisib at different concentrations. The 50% inhibitory concentration (IC@*RESULTS@#The cell survival rates were significantly decreased in a dose-dependent manner when the cells were treated with different doses of ADM (0.001-10.000 mg/L ). The IC@*CONCLUSIONS@#Idelalisib exerts effect on inhibition of the proliferation in myeloid leukemia K562 and K562/ADM cells, which may partially reverse the drug resistance of K562/ADM cells to ADM. The mechanisms for the effect of idelalisib may be related to increasing the accumulation of ADM and inducing the cell apoptosis in the K562 and K562/ADM cells.
Subject(s)
Humans , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Cell Proliferation , Doxorubicin/pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , K562 Cells , Leukemia, Myeloid , Purines , QuinazolinonesABSTRACT
Nitrogen-containing heterocycles such as quinoline, quinazolinones and indole are scaffolds of natural products and have broad biological effects. During the last years those structures have been intensively synthesized and modified to yield new synthetic molecules that can specifically inhibit the activity of dysregulated protein kinases in cancer cells. Herein, a series of newly synthesized isoquinolinamine (FX-1 to 8) and isoindoloquinazolinone (FX-9, FX-42, FX-43) compounds were evaluated in regards to their anti-leukemic potential on human B- and T-acute lymphoblastic leukemia (ALL) cells. Several biological effects were observed. B-ALL cells (SEM, RS4;11) were more sensitive against isoquinolinamine compounds than T-ALL cells (Jurkat, CEM). In SEM cells, metabolic activity decreased with 10 μM up to 26.7% (FX-3), 25.2% (FX-7) and 14.5% (FX-8). The 3-(p-Tolyl) isoquinolin-1-amine FX-9 was the most effective agent against B- and T-ALL cells with IC50 values ranging from 0.54 to 1.94 μM. None of the tested compounds displayed hemolysis on erythrocytes or cytotoxicity against healthy leukocytes. Anti-proliferative effect of FX-9 was associated with changes in cell morphology and apoptosis induction. Further, influence of FX-9 on PI3K/AKT, MAPK and JAK/STAT signaling was detected but was heterogeneous. Functional inhibition testing of 58 kinases revealed no specific inhibitory activity among cancer-related kinases. In conclusion, FX-9 displays significant antileukemic activity in B- and T-ALL cells and should be further evaluated in regards to the mechanisms of action. Further compounds of the current series might serve as templates for the design of new compounds and as basic structures for modification approaches.
Subject(s)
Humans , Apoptosis , Biological Products , Erythrocytes , Hemolysis , Inhibitory Concentration 50 , Leukocytes , Phosphotransferases , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Protein Kinases , QuinazolinonesABSTRACT
<p><b>BACKGROUND</b>It is well documented that sevoflurane postconditioning (SP) has a significant myocardial protection effect. However, the mechanisms underlying SP are still unclear. In the present study, we investigated the hypothesis that the Pim-1 kinase played a key role in SP-induced cardioprotection by regulating dynamics-related protein 1 (Drp1).</p><p><b>METHODS</b>A Langendorff model was used in this study. Seventy-two rats were randomly assigned into six groups as follows: CON group, ischemia reperfusion (I/R) group, SP group , SP+proto-oncogene serine/threonine-protein kinase 1 (Pim-1) inhibitor II group, SP+dimethylsufoxide group, and Pim-1 inhibitor II group (n = 12, each). Hemodynamic parameters and infarct size were measured to reflect the extent of myocardial I/R injury. The expressions of Pim-1, B-cell leukemia/lymphoma 2 (Bcl-2) and cytochrome C (Cyt C) in cytoplasm and mitochondria, the Drp1 in mitochondria, and the total Drp1 and p-Drp1ser637 were measured by Western blotting. In addition, transmission electron microscope was used to observe mitochondrial morphology. The experiment began in October 2014 and continued until July 2016.</p><p><b>RESULTS</b>SP improved myocardial I/R injury-induced hemodynamic parametric changes, cardiac function, and preserved mitochondrial phenotype and decreased myocardial infarct size (24.49 ± 1.72% in Sev group compared with 41.98 ± 4.37% in I/R group; P< 0.05). However, Pim-1 inhibitor II significantly (P < 0.05) abolished the protective effect of SP. Western blotting analysis demonstrated that, compared with I/R group, the expression of Pim-1 and Bcl-2 in cytoplasm and mitochondria as well as the total p-Drp1ser637 in Sev group (P < 0.05) were upregulated. Meanwhile, SP inhibited Drp1 compartmentalization to the mitochondria followed by a reduction in the release of Cyt C. Pretreatment with Pim-1 inhibitor II significantly (P < 0.05) abolished SP-induced Pim-1/p-Drp1ser637 signaling activation.</p><p><b>CONCLUSIONS</b>These findings suggested that SP could attenuate myocardial ischemia-reperfusion injury by increasing the expression of the Pim-1 kinase. Upregulation of Pim-1 might phosphorylate Drp1 and prevent extensive mitochondrial fission through Drp1 cytosolic sequestration.</p>
Subject(s)
Animals , Male , Rats , Dynamins , Metabolism , Hemodynamics , Ischemic Postconditioning , Methods , Methyl Ethers , Therapeutic Uses , Mitochondria , Metabolism , Myocardial Reperfusion Injury , Metabolism , Proto-Oncogene Proteins c-pim-1 , Metabolism , Quinazolinones , Pharmacology , Rats, Sprague-DawleyABSTRACT
Mitochondrial fission can occur via activation of dynamin-related protein 1 (Drp1), which participates in the mitochondrial membrane scission process. The present study was designed to investigate the effect of angiotensin II (AngII) on mitochondrial fission and fusion in human umbilical vascular endothelial cells (HUVECs). And we further inquire into whether Mdivi-1, a newly identified pharmacological inhibitor of Drp1, can prevent endothelial dysfunction induced by AngII. The HUVECs were treated with AngII alone or in combination with Mdivi-1. Western blot was used to detect protein expressions of Drp1, endothelial nitric oxide synthase (eNOS) and apoptosis-related enzymes. MitoTracker Red and JC-1 dye were used to detect mitochondrial morphology and membrane potential, respectively. DCFH-DA probe was used to access intracellular reactive oxygen species (ROS) generation. Transwell assay was used to evaluate cell migration. Annexin V/PI staining was used to assess cellular apoptosis. The results showed that, in cultured HUVECs, AngII (1 × 10mol/L, 12 h) treatment significantly upregulated the expression of Drp1 followed by increased apoptosis and decreased eNOS expression. The treatment of AngII resulted in a change in mitochondrial morphology from elongated to uniformly punctate organelles, which was accompanied by decreased mitochondrial membrane potential. Furthermore, Mdivi-1 significantly protected against AngII-induced endothelial dysfunction, as shown by increased mitochondrial membrane potential and eNOS expression, reduced ROS level, decreased apoptosis and migration ability. Taking together, our data suggest that inhibition of Drp1 with Mdivi-1 can restore AngII-induced endothelial dysfunction.
Subject(s)
Humans , Angiotensin II , Apoptosis , Cells, Cultured , Endothelial Cells , Fluoresceins , Membrane Potential, Mitochondrial , Microtubule-Associated Proteins , Mitochondria , Mitochondrial Proteins , Nitric Oxide Synthase Type III , QuinazolinonesABSTRACT
<p><b>OBJECTIVE</b>To investigate the effect of CAL-101, a selective inhibitor of PI3Kδ, in combination with bortezomib on the proliferation and apoptosis in human mantle cell lymphoma cell lines Z138, HBL-2 and Jeko-1 in vitro, to explore its mechanisms and provide the foundation for effective treatment strategies against mantle cell lymphoma.</p><p><b>METHODS</b>MTT assay was applied to detect the inhibitory effects of CAL-101 and bortezomib either alone or combined on Z138, HBL-2 and Jeko-1 cells. Calcusyn software was used to analyze the synergistic cytotoxicity. Western blot was used to detect the expression of PI3K-p110σ and p-Akt, Akt, p-ERK and ERK proteins after the cells were exposed to different concentrations of CAL-101. Flow cytometry was employed to assess the apoptosis rate. NF-κB kit was used to determine the changes of location of NF-κB P65, and Western blot was applied to detect the level of caswpase-3 and the phosphorylation of Akt in different groups.</p><p><b>RESULTS</b>CAL-101 and BTZ inhibited the proliferation of Z138, HBL-2 and Jeko-1 cells in a dose- and time-dependent manner. CAL-101/BTZ combination induced significantly synergistic cytotoxicity in the MCL cells. The results of Western blot assay showed that CAL-101 significantly blocked the phosphorylation of Akt and ERK in the MCL cell lines. In addition, CAL-101 combined with BTZ induced pronounced apoptosis (P < 0.01). For example, after the Z138 cells exposed to the drugs for 48 h, the apoptosis rates of the control, CAL-101, BTZ and CAL-101 + BTZ groups were: (2.6 ± 1.8)%, (40.0 ± 3.0)%, (34.0 ± 1.0)%, and (67.4 ± 1.0)%, respectively; and when drug treatment was given to HBL-2 cells over 96 h, the apoptosis rates of these four cell groups were (7.4 ± 0.6)%, (30.7 ± 5.7)%, (12.0 ± 1.0)%, and (85.0 ± 4.0)%, respectively. The combination therapy contributed to the enhanced inactivity of nuclear factor-κB (NF-κB) and Akt inactivation in the MCL cell lines (P < 0.05), however, the casepase-3 activity was up-regulated.</p><p><b>CONCLUSIONS</b>The combination of CAL-101 and bortezomib is muchmore effective in inhibiting proliferation and promoting apoptosis of mantle cell lymphoma cell lines (Z138, HBL-2 and Jeko-1), which may be mediated through inhibiting PI3K/Akt signaling pathway and the transcription of NF-κB.</p>
Subject(s)
Humans , Antineoplastic Agents , Pharmacology , Antineoplastic Combined Chemotherapy Protocols , Pharmacology , Apoptosis , Blotting, Western , Boronic Acids , Bortezomib , Pharmacology , Caspase 3 , Metabolism , Cell Line, Tumor , Cell Proliferation , Class Ia Phosphatidylinositol 3-Kinase , Dose-Response Relationship, Drug , Drug Synergism , Formazans , Lymphoma, Mantle-Cell , Drug Therapy , Pathology , MAP Kinase Signaling System , NF-kappa B , Metabolism , Neoplasm Proteins , Metabolism , Phosphatidylinositol 3-Kinases , Metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt , Metabolism , Purines , Pharmacology , Pyrazines , Quinazolinones , Pharmacology , Signal Transduction , Software , Tetrazolium SaltsABSTRACT
<p><b>OBJECTIVE</b>To investigate the effects of Th1/Th17 cell imbalance on the pathogenesis of acute graft-versus-host disease (GVHD) in mice.</p><p><b>METHODS</b>In a murine GVHD model of C57BL/6 (H-2(b)), a low dose of halofuginone (HF) was applied for treating the recipients in order to result in Th1/Th17 imbalance. Rechipient mice were divided into GVHD group (without HF intervention) and GVHD plus HF group (treated by HF). The recipients were monitored for survival rate, clinical scores of acute GVHD, contents of circulatory Th1 and Th17 cells, Th1/Th17 ratio and serum level of IFN-γ and IL-17A. Expression levels of IFN-γ and IL-17A in target organs were analyzed by using real-time PCR, and the target organs were delivered for histological examinations.</p><p><b>RESULTS</b>Recipients treated with HF showed that all the mortality, circulatory Th1/Th17 ratio and clinical score were higher than those in the mice without HF intervention (P < 0.05). Circulatory Th1/Th17 ratio positively correlates with clinical score (P < 0.001). HF administration reduces the expression level of intestinal IL-17A and increases intrahepatic and intestinal IFN-γ level (P < 0.05), HF treatment aggravates GVHD in liver and small intestine with augmented hepatic and intestinal inflammation.</p><p><b>CONCLUSION</b>Th1/Th17 imbalance contributes to the pathogenesis of acute GVHD.</p>
Subject(s)
Animals , Mice , Disease Models, Animal , Graft vs Host Disease , Allergy and Immunology , Interferon-gamma , Blood , Interleukin-17 , Blood , Mice, Inbred BALB C , Mice, Inbred C57BL , Piperidines , Quinazolinones , Th1 Cells , Cell Biology , Th17 Cells , Cell BiologyABSTRACT
The aim of the present research was to synthesise several novel fluorinated quinazoline-sulphonamide derivatives and to evaluate their in vitro cytotoxic activity. Eight compounds were synthesised. The compounds' anticancer activities were determined through the [3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyltetrazolium bromide] [MTT] assay using a three-cell-line panel consisting of National Cancer Institute [NCI] lung cancer cells, Michigan Cancer Foundation-7 [MCF-7] breast cancer cells, and Human Embryonic Kidney-293 [HEK-293] normal kidney cell. The values of C log P correlations were determined to interpret the results. One compound exhibited significant anticancer activity with low toxicity compared with the methotrexate as the reference drug. The biological screening showed good to moderate anticancer activity for the title compounds compared with the reference drug. The reference drug exhibited an IC[50] value of 2.4 micro M, whereas compound 9, which was identified as the most active compound, exhibited an IC[50] value of 2.51 micro M on the NCI cell line. The other compounds showed IC[50] values that ranged from 2.89 to 46.34 micro M on the three cell lines. The newly synthesized compounds had lower toxicity on the normal cell line than did methotrexate. The newly synthesized compounds may provide a valuable template for future design and optimization to produce analogues that act as more active anticancer agents
Subject(s)
Quinazolinones/chemical synthesis , Sulfonamides/chemical synthesis , Halogenation , CytotoxinsABSTRACT
<p><b>OBJECTIVE</b>To investigate the proliferation inhibitory role and mechanism of PI3Kδ inhibitor CAL-101 on multiple myeloma (MM) cells, and to provide new therapeutic options for MM treatment.</p><p><b>METHODS</b>MM cell lines U266 and RPMI8226 cells were treated with various concentrations of CAL-101. MTT assay and CalcuSyn software were performed to determine the inhibitory effect of CAL-101 and the synergistic effect with PCI- 32765, SAHA (suberoylanilide hydroxamic acid), BTZ (Bortezomib) on MM cells. The protein expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ processed by CAL-101 were analyzed by Western blot.</p><p><b>RESULTS</b>CAL-101 at concentration of 15, 20, 25, 30 and 40 μmol/L could induce significant dose-dependent proliferation inhibition on U266 cells after treatment for 48 hours. The cell proliferation inhibition rates were (33.54 ± 1.23)%, (41.72 ± 1.78)%, (53.67 ± 2.01)%, (68.97 ± 2.11)% and (79.25 ± 1.92)%, respectively. Similar results were found in RPMI8226 cell line. Western blots showed high expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ in cell lines and MM primary cells. p-AKT and p-ERK protein expression levels were down-regulated significantly by CAL-101 treatment. Synergistic effect has been verified between CAL-101 and PCI-32765, SAHA and Bortezomib in U266 cell line, and PCI-32765, Bortezomib in RPMI8226 cell line with CI values less than 1.</p><p><b>CONCLUSION</b>CAL-101 could inhibit proliferation of MM cell lines. High levels of p-AKT, p-ERK, AKT, ERK and PI3Kδ protein expression were observed in both cell lines and primary cells. Down-regulation of p-AKT and p-ERK probably related with the mechanism of CAL-101 in MM cell proliferation inhibition. CAL-101 has significant synergistic effect with PCI-32765, SAHA and BTZ.</p>
Subject(s)
Humans , Boronic Acids , Bortezomib , Cell Line, Tumor , Cell Proliferation , Down-Regulation , Multiple Myeloma , Pathology , Phosphatidylinositol 3-Kinases , Protein Kinase Inhibitors , Pharmacology , Purines , Pharmacology , Pyrazines , Pyrazoles , Pyrimidines , Quinazolinones , PharmacologyABSTRACT
Poly(ADP-ribose) polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. It can polymerize ADP-ribose units on its substrate proteins which are involved in the regulation of DNA repair. In this work, a novel series of para-substituted 1-benzyl-quinazoline-2, 4 (1H, 3H)-diones was designed and synthesized, and the inhibitory activities against PARP-1 of compounds 7a-7e, 8a-8f, 9a-9c and 10a-10c were evaluated. Of all the tested compounds, nine compounds displayed inhibitory activities with IC50 values ranging from 4.6 to 39.2 micromol x L(-1). In order to predict the binding modes of the potent molecules, molecular docking was performed using CDOCKER algorithm, and that will facilitate to further develop more potent PARP-1 inhibitors with a quinazolinedione scaffold.
Subject(s)
Antineoplastic Agents , Chemistry , Pharmacology , Drug Design , Enzyme Inhibitors , Chemistry , Pharmacology , Molecular Docking Simulation , Molecular Structure , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases , Quinazolinones , Chemistry , Pharmacology , Structure-Activity RelationshipABSTRACT
CAL-101 is a selective inhibitor of the phosphatidylinositol-3 kinase (PI3K), it inhibits the survival, proliferation and migration of tumor cells by directly inducing apoptosis and inhibiting micro-environmental interactions. It has been determined that the P110δ isoforms of PI3K expressed primarily in cells of hematopoietic lineage, such as B and T cells. This review focuses on the target, mechanism of action, the use and prospect of CAL-101 in tumors of blood and lymph systems.
Subject(s)
Animals , Humans , Class Ia Phosphatidylinositol 3-Kinase , Hematologic Neoplasms , Drug Therapy , Purines , Pharmacology , Therapeutic Uses , Quinazolinones , Pharmacology , Therapeutic Uses , Signal TransductionABSTRACT
Acute coronary syndromes (ACS) are the commonest acute manifestation of coronary artery disease and a major cause of hospitalization and death. Plaque rupture and subsequent platelet activation are the key factors in its pathogenesis. Platelet inhibitors are crucial in the management of ACS. Aspirin remains the standard antiplatelet but use of dual antiplatelet drugs is beneficial in ACS. Platelet P2Y12 receptor inhibitors are an important group of antiplatelet compounds that can be combined with aspirin in the management of ACS. P2Y12 inhibitors may belong to the thienopyridine or nonthienopyridine group of compounds. The former (clopidogrel, prasugrel) combine irreversibly with the receptor and therefore have a prolonged duration of action. On the other hand, the non-thienopyridine compounds (ticagrelor, elinogrel) have a reversible action and hence a shorter duration of action. Several new compounds in this group have become or are likely to become available. The newer agents have a more uniform and complete antiplatelet effect and are much less likely to be affected by genetic variability of CYP2C19 enzyme activity compared with that of clopidogrel. Large phase 3 trials have shown that ticagrelor and prasugrel reduce major cardiovascular events in ACS compared to clopidogrel when given in addition to aspirin. This is accompanied by some increase in bleeding. This review discusses the properties, clinical profile and possible place of P2Y12 receptor inhibitors in clinical practice.
Subject(s)
Acute Coronary Syndrome/drug therapy , Adenosine/analogs & derivatives , Adenosine/therapeutic use , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Humans , Piperazines/therapeutic use , Purinergic P2Y Receptor Antagonists/therapeutic use , Quinazolinones/therapeutic use , Sulfonamides/therapeutic use , Thiophenes/therapeutic use , Ticlopidine/analogs & derivatives , Ticlopidine/therapeutic useABSTRACT
Opioids are an important group of analgesics that are used extensively to control sever pains. Physical dependence to these drugs is a major problem. There are a few studies regarding the involvement of cholecyctokinin [CCK] in the withdrawal syndromes of opioids. In the present study, the effects of CCK agonist and antagonist on the number of jumping of morphine dependent mice were evaluated. In this experimental study, the effects of CCK-8 and LY225910 [selective CCK2 receptor antagonist] on jumpings of mice after morphine dependence were evaluated. Mice were injected with morphine three times a day [50, 50 and 75 mg/kg] for three days; at the forth day they received 50 mg/kg morphine. Injection of naloxone [5 mg/kg] induced withdrawal signs such as jumping. The experimental groups received different doses of CCK-8 [0.1, 0.3 and 0.6 mg/kg] and LY225910 [0.01, 0.5 and 1 mg/kg] with each injection of morphine. Injection of CCK-8 significantly decreased the naloxone-induced jumpings, while LY225910 did not have any significant effects on these jumpings. Based on the results of the present study, activation of CCK1 receptors probably is involved in morphine dependence. The results also confirm that injection of CCK but not CCK2 selective antagonist probably decreases the jumpings of mice following withdrawal syndrome of morphine
Subject(s)
Animals, Laboratory , Receptor, Cholecystokinin B/antagonists & inhibitors , Naloxone , Morphine Dependence , Mice , Cholecystokinin , Substance Withdrawal Syndrome , QuinazolinonesABSTRACT
A series of 4(3H)-quinazolinone derivatives bearing dithiocarbamate side chains have been synthesized through the reaction of 6-bromomethyl-2-methyl-4(3H)-quinazolinone with CS2 and various amines in the presence of anhydrous K3PO4, and their structures were confirmed with ESI-MS, H NMR, elemental analysis or HRMS. The target compounds 8a -8q were tested for their in vitro antitumor activity against human myelogenous leukaemia K562 and human Hela cell lines by means of colorimetric MTT assay. Among the tested compounds, 8q exhibited in vitro inhibitory activity against K562 and Hela cells with IC50 values of 0.5 and 12.0 micromol x L(-01), respectively. Therefore, compound 8q is worthy to be a lead compound for the design and synthesis of new antitumor agents.
Subject(s)
Humans , Antineoplastic Agents , Pharmacology , Ethylenebis(dithiocarbamates) , Chemistry , Pharmacology , HeLa Cells , Inhibitory Concentration 50 , K562 Cells , Molecular Structure , Quinazolinones , Chemistry , Pharmacology , Structure-Activity RelationshipABSTRACT
Antifibrotic therapies should preferentially be targeted to the activatedhepatic mesenchymal cells. Those cells resemble wound healing myofibroblasts and synthesize an excess of extracellular matrix [ECM] proteins. They derive from quiescent hepatic stellate cells [HSC] and portal/perivascular [myo-] fibroblasts [MF]. Whereas various agents have been shown to inhibit HSC/MF proliferation and collagen synthesis in vitro, only few of them are effective. Established in vivo models are rat secondary biliary fibrosis [chronic cholestatic liver disease] and reversion of fibrosis after withdrawal of a hepatotoxin like thioacetamide. The interferons [IFN-gamma>alpha, beta] have proven antiproliferative and fibrosuppressive activity on mesenchymal cells in culture. Retrospective data suggest that IFN- alpha therapy for hepatitis C can halt or even reverse fibrosis. This has to be confirmed by large randomized prospective studies, but an effect in biliary fibrosis is less probable. Strategies to inhibit the key profibrogenic cytokine TGF- beta, e.g. by soluble decoy receptors, or molecules that are involved in TGF- beta signal transduction are evolving but targeted approaches have to be used, in order to prevent unwanted side-effects. Novel agents are being developed in the form of orally available small molecule inhibitors [peptidomimetics]. These include antagonists of certain integrins [alpha gamma beta 3 or alpha gamma beta 6] that are involved in HSC/MF migration or TGF beta -activation, respectively, or of the endothelin A receptor that causes contraction and proliferation of activated HSC/MF. Future studies will have to show if and how far drug combination is effective in man, combined with reasonable costs and no or irrelevant side-effects. Some agents are antioxidants like silymarin, a defined mixture of flavonoids, sho-saiko-to which contains related compounds like baicalein, glitazones, phosphodiesterase inhibitors like pentoxifylline, inhibitors of the renin-angiotensin system, halofuginone and some immunosuppressants like mycophenolate mofetil and rapamycin. Drug targeting to the fibrogenic liver cells is now possible by use of small molecular ligands that bind to receptors which are specifically upregulated on activated HSC/MF. These ligands can be exploited as carriers for otherwise toxic drugs, antisense DNA or siRNAs directed against profibrogenic mRNAs, such as those against procollagen I or TGF beta 1. It is likely that liver fibrosis of different etiology will need different antifibrotic treatments. Quick progress in the clinical development of antifibrotic therapies can only be expected with the evolving validation of noninvasive, serological markers of fibrogenesis or fibrolysis