Metastasis suppressors: basic and translational advances

Tumor metastasis is a main contributor to death in cancer patients. In the last years, a new class of molecules that reduces the metastatic propensity has been identified: metastasis suppressors. These proteins regulate multiple steps in the metastatic cascade, including cell invasion, survival in the vascular and lymphatic circulation, and colonization of distant organ sites. As a consequence, they are very important therapeutic targets. This review discusses our current understanding of metastasis suppressors and how this knowledge might be useful to improve the treatment of cancer patients.     

Topoisomerase I poisons and suppressors as anticancer drugs

Inhibitors of topoisomerase I constitute a novel family of antitumor agents. The camptothecin derivatives topotecan and irinotecan represent new weapons in our arsenal for battling human cancer. These two drugs act specifically at the level of the topoisomerase I-DNA complex and stimulate DNA cleavage. This mechanism of action is not restricted to the camptothecins. Numerous topoisomerase I poisons including DNA minor groove binders such as Hoechst 33258 and DNA intercalators such as benzophenanthridine alkaloids and indolocarbazole derivatives have been discovered and developed. Another important group of topoisomerase I inhibitors contains drugs which prevent or reverse topoisomerase I-DNA complex formation. Many of these topoisomerase I suppressors are natural products (beta-lapachone, diospyrin, topostatin, topostin, flavonoids) which are believed to interact directly with the enzyme. This review is concerned with the different families of topoisomerase I poisons and suppressors. Their origin, chemical nature and mechanism of action are presented. The relationships between drug binding to DNA and topoisomerase I inhibition are discussed.     

MicroRNAs: small but potent oncogenes or tumor suppressors

MicroRNAs (miRNAs) are small, non-coding RNAs that modulate the expression of target mRNA. Many miRNAs are known to be up- or downregulated in a variety of cancers, suggesting a role for miRNAs in tumorigenesis. The correlation between the expression of miRNAs and their effects on target oncogenes, on tumorigenesis and on the proliferation of cancer cells is beginning to gain experimental evidence. For example, the miRNA (miR)-17-92 cluster has been characterized as an oncogene, while let-7 represses Ras and miR-15a/-16-1 represses Bcl-2, thereby acting as tumor suppressors. Thus, an oncogenic or tumor suppressive miRNA may have potential as a therapeutic target to control cancers. This review will discuss the relationship between miRNAs and tumorigenesis, and the potential for modulating miRNAs for the treatment of cancer.     

Monoamines as immunomodulators: importance of suppressors and helpers of the bone marrow

The intraimmune pathways and mechanisms of action of the serotoninergic and dopaminergic systems in exerting a modulating effect upon immunogenesis are presented. Experiments were carried out in mice immunized with sheep red blood cells (1 X 10(7); 5 X 10(6)). Participation of the hypothalamic-pituitary complex in the monoaminergic mechanisms of stimulation and inhibition of rosette formation was revealed. Dissection of the pituitary stalk prevented stimulation of rosette formation by apomorphine (1 mg/kg i.p) and bupropion (20 mg/kg) and the reduction of the immune response by haloperidol (1 mg/kg), 5-hydroxytryptophan (300 mg/kg) and serotonin (50 mg/kg). The results of syngeneic cellular transfer of different immunocompetent organs showed that serotonin injection induced an increase in B-suppressor activity of bone marrow cells, reaching maximal value in the inductive period (day 3 of the immune response). B-Lymphocyte suppression in donors not treated with serotonin peaked on day 5 of the immune response. Stimulation of the immune response under activation of the dopaminergic system after apomorphine administration was provided by an increase in T-helper activity in the bone marrow cells, mainly with respect to IgM-response. The suppressive activity of bone marrow T cells on IgM- and IgG-immune responses was increased in nonimmunized donors treated with serotonin or haloperidol. The mechanisms of neurochemical multichannel immunomodulation by means of redistribution of cellular populations resulting in an increase in suppressors or helpers in bone marrow are discussed.     

Suppressing renal NADPH oxidase to treat diabetic nephropathy

Renal nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase is an important source of oxidative stress and its expression is enhanced in the glomerulus and distal tubules of diabetic nephropathy. High glucose-induced protein kinase C signalling or renal angiotensin II signalling increases the membrane translocation of cytosolic component p47phox. NADPH oxidase-derived reactive oxygen species (ROS) in the podocytes damage the glomerular basement membrane and the slit diaphragm causing proteinuria, and mesangial and glomerular endothelial NADPH oxidase increase TGF-β and cause collagen and fibronectin accumulation. Tubular NADPH oxidase stimulated by angiotensin II or aldosterone contributes to sodium retention and to tubulointerstitial damage. Thus, inhibition of the renal renin–angiotensin II–aldosterone system with angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blocker or selective aldosterone inhibitor indirectly suppresses NADPH oxidase reducing renal ROS, proteinuria and glomerulosclerosis. Statins are also effective in blocking the membrane translocation of Rac, especially in diabetes with hypercholesterolemia where ROS is produced by the intrinsic NADPH oxidase and by the activated macrophages. A medical herb, picrorhiza, inhibits the membrane translocation of p47phox, is a specific inhibitor of NADPH oxidase and, more so than superoxide dismutase mimetics, may be a promising strategy for the treatment of diabetic nephropathy.     

Suppressing renal NADPH oxidase to treat diabetic nephropathy

Renal nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase is an important source of oxidative stress and its expression is enhanced in the glomerulus and distal tubules of diabetic nephropathy. High glucose-induced protein kinase C signalling or renal angiotensin II signalling increases the membrane translocation of cytosolic component p47phox. NADPH oxidase-derived reactive oxygen species (ROS) in the podocytes damage the glomerular basement membrane and the slit diaphragm causing proteinuria, and mesangial and glomerular endothelial NADPH oxidase increase TGF-beta and cause collagen and fibronectin accumulation. Tubular NADPH oxidase stimulated by angiotensin II or aldosterone contributes to sodium retention and to tubulointerstitial damage. Thus, inhibition of the renal renin-angiotensin II-aldosterone system with angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blocker or selective aldosterone inhibitor indirectly suppresses NADPH oxidase reducing renal ROS, proteinuria and glomerulosclerosis. Statins are also effective in blocking the membrane translocation of Rac, especially in diabetes with hypercholesterolemia where ROS is produced by the intrinsic NADPH oxidase and by the activated macrophages. A medical herb, picrorhiza, inhibits the membrane translocation of p47phox, is a specific inhibitor of NADPH oxidase and, more so than superoxide dismutase mimetics, may be a promising strategy for the treatment of diabetic nephropathy.     

A Strategy for Suppressing Redox Stress within Mitochondria

相似文献   

Suppressing NADPH oxidase-dependent oxidative stress in the vasculature with nitric oxide donors

1. Reactive oxygen species produced in the vasculature, including superoxide anion, contribute to the pathogenesis of cardiovascular disease states, such as atherosclerosis. A critical source of superoxide is vascular NADPH oxidase and upregulation of this enzyme brings about the oxidative stress underlying atherosclerosis. Excessive superoxide in arteries directly inactivates endothelium-derived nitric oxide (NO), compromising its vasoprotective effects. 2. Given that a reduction in NO bioavailability is key in the pathophysiology of atherosclerosis, replacement of NO by exogenously administered NO donors may restore the deficit in NO during disease. Although the organic nitrate family of NO donors is often the first choice for the acute management of symptoms of atherosclerosis and angina pectoris, most of the compounds in this class are unsuitable for long-term therapy because they cause oxidative stress by activation and upregulation of vascular NADPH oxidase and induce tolerance to subsequent nitrate treatment and endogenous NO. These problems of nitrates have not only limited their therapeutic exploitation, but have also stifled interest in newer-generation NO donors. 3. Recent evidence indicates that, in stark contrast with the organic nitrates, the newer-age diazeniumdiolate NONOate class of NO donors suppress vascular NADPH oxidase-dependent superoxide production and are less likely to induce tolerance, making them more suitable for suppression of oxidative stress in atherosclerosis. 4. Here, it is hypothesized that NONOates provide a novel means of suppressing NADPH oxidase-dependent oxidative stress to restore vascular NO levels to prevent, and even reverse, atherosclerosis.     

Prostacyclin and beraprost sodium as suppressors of activated rat polymorphonuclear leukocytes

Beraprost sodium (beraprost) is a stable analogue of prostaglandin I2 (PGI2), which can be administrated orally. In the present study, the effect of beraprost on the activation process of polymorphonuclear leukocytes (PMNs) was examined in vitro. Beraprost effectively inhibited chemotaxis of PMNs induced by formyl-methionyl-leucyl-phenylalanine (FMLP). Like prostaglandin E2 (PGE2), beraprost elevated intracellular cAMP level and inhibited the influx of extracellular Ca2+ in PMNs. The concentration-response curves showed that the inhibitory effect of beraprost on chemotaxis was correlated with the increment of intracellular cAMP level of the PMNs and inhibition of influx of extracellular Ca2+. Beraprost also inhibited inositol phospholipid metabolic turnover and superoxide anion production of PMNs induced by FMLP at relatively high concentration. These results suggest that the inhibitory effect of beraprost on the PMN function especially chemotaxis is mediated through the elevation of the intracellular cAMP level, which interferes with the signal transduction process probably through the inhibition of Ca2+ mobilization in PMNs. The above-mentioned effects of beraprost were also the case with PGI2. The potency of beraprost was comparable to PGI2 in the present study. Considering its stability, these results thus raise a possibility that beraprost might exert anti-inflammatory effect in vivo.     

Histone deacetylase inhibitors as suppressors of bone destruction in inflammatory diseases

Objectives Despite progress in developing many new anti‐inflammatory treatments in the last decade, there has been little progress in finding treatments for bone loss associated with inflammatory diseases, such as rheumatoid arthritis and periodontitis. For instance, treatment of rheumatic diseases with anti‐tumour necrosis factor‐alpha agents has been largely successful in reducing inflammation, but there have been varying reports regarding its effectiveness at inhibiting bone loss. In addition, there is often a delay in finding the appropriate anti‐inflammatory therapy for individual patients, and some therapies, such as disease modifying drugs, take time to have an effect. In order to protect the bone, adjunct therapies targeting bone resorption are being developed. This review focuses on new treatments based on using histone deacetylase inhibitors (HDACi) to suppress bone loss in these chronic inflammatory diseases. Key findings A number of selected HDACi have been shown to suppress bone resorption by osteoclasts in vitro and in animal models of chronic inflammatory diseases. Recent reports indicate that these small molecules, which can be administered orally, could protect the bone and might be used in combination with current anti‐inflammatory treatments. Summary HDACi do have potential to suppress bone destruction in chronic inflammatory diseases including periodontitis and rheumatoid arthritis.     

急性炎症对黑色素瘤基质金属蛋白酶影响的研究

目的:研究急性炎症对黑色素瘤生长及肿瘤基质金属蛋白酶(MMP)-9和MMP-2的表达水平的影响.方法:采用C57BL小鼠,构建B16小鼠黑色素瘤动物模型,待肿瘤生长至0.5 cm2时构建伤口模型,分为单纯肿瘤组(对照组)和伤口+肿瘤组(实验组),比较肿瘤体积大小,免疫组织化学染色检测肿瘤组织MMP-2和MMP-9的表达,明胶酶谱法分析MMP-2和MMP-9活性.结果:(1)实验组肿瘤体积在5 d和7 d时明显小于对照组(P<0.05或P<0.01).(2)在造模后7 d实验组MMP-2的细胞阳性表达率低于对照组(P<0.01),11 d时2组比较差异无统计学意义(P>0.05);7 d和11 d实验组MMP-9阳性表达率均低于对照组(P<0.01).实验组MMP-2和MMP-9酶活性在7 d时低于对照组(P<0.01),11 d时2组比较差异无统计学意义(P>0.05).结论:急性炎症早期可影响肿瘤组织MMPs的表达,明显抑制黑色素瘤生长;而急性炎症晚期则对黑色素瘤生长和MMPs失去抑制作用.     

Effects of specific chemical suppressors of plasminogen activator inhibitor-1 in cardiovascular diseases

INTRODUCTION: plasminogen activator inhibitor-1 (PAI-1) is critical in thrombus formation and inflammation. Although these are essential pathological features of cardiovascular diseases, the effects of PAI-1 inhibition against the development of cardiovascular remodeling have not been well studied. AREAS COVERED: the review explores the therapeutic value of PAI-1 in the progression of various cardiovascular diseases. To date, the authors have reported that a novel PAI-1 inhibitor suppressed the development of experimental autoimmune myocarditis, vascular remodeling after arterial injury, and heart transplant rejection using rodent models. Pathologically, the PAI-1 inhibitor improved histological remodeling of myocardium and arteries with suppression of inflammation and thrombus formation. EXPERT OPINION: PAI-1 inhibitors appear to exhibit potent effects on the prevention of adverse tissue remodeling. However, PAI-1 is a multifunctional protein and more research is needed to further elucidate the association between PAI-1 expression and cardiovascular disease.     

22-Hydroxycholesterol derivatives as HMG CoA reductase suppressors and serum cholesterol lowering agents

A series of 22-hydroxycholesterol derivatives with a modified side chain terminus was prepared. These agents were evaluated in vitro and in vivo for their ability to suppress HMG CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. In tissue culture assays, 22-hydroxycholesterol as well as the side chain modified analogues were potent inhibitors of HMG CoA reductase. However, only those sterols with a modified side chain terminus were effective suppressors of liver reductase when administered ig to rats. 22-Hydroxy-25-methylcholesterol (4a) and 25-fluoro-22-hydroxycholesterol (15a) significantly lowered serum cholesterol levels when administered ig to primates; 25-chloro-22-hydroxycholesterol (15b) and the analogue with a cyclopropyl terminus, 20b, were ineffective. The cholesterol-lowering sterols did not significantly alter lipoprotein levels; however, the two compounds have been shown to inhibit acyl-coenzyme A:cholesterol acyl-transferase (ACAT) in tissue culture studies.     

Identification of Stabilized Dynorphin Derivatives for Suppressing Tolerance in Morphine-Dependent Rats

PURPOSE: Modulatory actions on morphine-induced effects, such as tolerance and withdrawal, have been noted for dynorphin A(1-13) [Dyn A(1-13)] and similar peptides. These are currently of limited therapeutic potential due to extensive metabolism by human metabolic enzymes resulting in a half-life of less than 1 min in human plasma. The purpose of this study was to identify stabilized dynorphin A (Dyn A) derivatives, to determine their metabolic routes in human plasma, and to assess whether the pharmacodynamic activity is retained. METHODS: The stability of peptides in human plasma was tested using in vitro metabolism studies with and without enzyme inhibitors. Identification of the generated metabolites was performed by mass spectrometry after high performance liquid chromatography (HPLC) separation. The in vivo activity of a stabilized dynorphin was tested by tail-flick assay in morphine-tolerant rats. RESULTS: Though amidation of the Dyn A(1-13) was able to stop the majority of C-terminal degradation, metabolism of Dyn A(1-10) amide continued by captopril sensitive enzymes, suggesting that Dyn A(1-13) amide is a better candidate for additional stabilization. Two Dyn A(1-13) amide derivatives further stabilized at the N-terminal end, [D-Tyr1]-Dyn A(1-13) amide and [N-Met-Tyr1]-Dyn A(1-13) amide, showed half-lives in plasma of 70 and 130 min, respectively. The most stable derivative [N-Met-Tyr1]-Dyn A(1-13) amide was tested successfully for retention of the pharmacological activity in modulating antinociceptive activity. CONCLUSIONS: [N-Met-Tyr1]-Dyn A(1-13) amide showed significant stability and antinociceptive activity in the tail-flick test, thus pointing to the clinical potential of this derivative in the management of pain as well as its potential activity in suppressing opiate tolerance and withdrawal.     

The tumor suppressors pRB and p53 as regulators of adipocyte differentiation and function

Background: The retinoblastoma protein (pRB) and p53 are crucial members of regulatory networks controlling the cell cycle and apoptosis, and a hallmark of virtually all cancers is dysregulation of expression or function of pRB or p53. Although they are best known for their role in cancer development, it is now evident that both are implicated in metabolism and cellular development. Objective/methods: To review the role of pRB and p53 in adipocyte differentiation and function emphasizing that pRB and p53, via their effects on adipocyte development and function, play a role in the regulation of energy metabolism and homeostasis. Results/conclusions: pRB is required for adipose conversion and also involved in determining its mitochondrial capacity. p53 inhibits adipogenesis and results suggest that it is involved in maintaining function of adipose tissue.