salicylates and Neoplasms

The Ras oncogene transmits signals, which regulate various cellular processes including cell motility, differentiation, growth and death. Since Ras signalling is abnormally activated in more than 30% of human cancers, Ras and its downstream signalling pathways are considered good targets for therapeutic interference. Ras is post-translationally modified by the addition of a farnesyl group, which permits its attachment to the plasma membrane. Exploiting this knowledge, a synthetic Ras inhibitor, S-trans, trans-farnesylthiosalicylic acid (FTS; Salirasib), was developed. FTS resembles the farnesylcysteine group of Ras, and acts as an effective Ras antagonist. In the present review, the effect of FTS in combination with various other drugs, as tested in vitro and in vivo, and its therapeutic potential are discussed. As reviewed, FTS cooperates with diverse therapeutic agents, which significantly improves treatment outcome. Therefore, combinations of FTS with other agents have a potential to serve as anti-cancer or anti-inflammatory therapies.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Farnesol; Humans; Neoplasms; Salicylates; Signal Transduction

Epigenetic processes and miRNAs have been recognized as new targets for anticancer drug design. However, old multi-target drugs such as aspirin may also target epigenetic processes.. This review aims to provide an overview of our current knowledge on the modulation of epigenetic processes by aspirin and other non steroidal anti-inflammatory agents (NSAIDs) and their implications for cancer treatment and chemoprevention.. In vitro and in vivo studies, as well as primary patient data, suggest that aspirin and other NSAIDs reverse tumour suppressor gene hypermethylation in cancer tissues. It must be emphasized that, at this point in time, patient data are limited and DNA hypermethylation reversal has been investigated, but not tumour suppressor gene activation. In addition, evidence from experimental and patient data suggests that aspirin and NSAIDs may also reverse global DNA hypomethylation. At the histone level, both induction and inhibition of deacetylases by aspirin have been reported. Also, direct acetylation of histones by aspirin has been reported, while the natural salicylate anacardic acid has been found to inhibit histone acetyltransferase p300 both in vitro and in vivo, and to regulate gene expression through modulation of histone acetylation. Salicylates and other NSAIDs may also down-regulate miRNAs with oncogene-like functions or up-regulate miRNAs with tumour suppressor-like functions. Up till now, clinical trials have been aimed at investigating the effect of salicylates and NSAIDs on a limited number of miRNAs.. So, although the existing evidence is still limited, evidence is accumulating that epigenetic targets may represent nodal targets for the anti-proliferative actions of salicylates and NSAIDs. This, in turn, may have implications for cancer chemoprevention and treatment. Undoubtedly, this notion requires further investigation, but if proved correct, it could lead to the design of less toxic agents that target epigenetic processes as part of existing or novel multi-targeted treatment modalities.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Salicylates

The Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS, Salirasib®) interferes with Ras membrane interactions that are crucial for Ras-dependent signaling and cellular transformation. FTS had been successfully evaluated in clinical trials of cancer patients. Interestingly, its effect is mediated by targeting Ras chaperones that serve as key coordinators for Ras proper folding and delivery, thus offering a novel target for cancer therapy. The development of new FTS analogs has revealed that the specific modifications to the FTS carboxyl group by esterification and amidation yielded compounds with improved growth inhibitory activity. When FTS was combined with additional therapeutic agents its activity toward Ras was significantly augmented. FTS should be tested not only in cancer but also for genetic diseases associated with abnormal Ras signaling, as well as for various inflammatory and autoimmune disturbances, where Ras plays a major role. We conclude that FTS has a great potential both as a safe anticancer drug and as a promising immune modulator agent.

Topics: Animals; Antineoplastic Agents; Farnesol; Humans; Immunotherapy; Molecular Chaperones; Neoplasms; ras Proteins; Salicylates; Signal Transduction

The Eph receptors are a large family of receptor tyrosine kinases. Their kinase activity and downstream signaling ability are stimulated by the binding of cell surface-associated ligands, the ephrins. The ensuing signals are bidirectional because the ephrins can also transduce signals (known as reverse signals) following their interaction with Eph receptors. The ephrin-binding pocket in the extracellular N-terminal domain of the Eph receptors and the ATP-binding pocket in the intracellular kinase domain represent potential binding sites for peptides and small molecules. Indeed, a number of peptides and chemical compounds that target Eph receptors and inhibit ephrin binding or kinase activity have been identified. These molecules show promise as probes to study Eph receptor/ephrin biology, as lead compounds for drug development, and as targeting agents to deliver drugs or imaging agents to tumors. Current challenges are to find (1) small molecules that inhibit Eph receptor-ephrin interactions with high binding affinity and good lead-like properties and (2) selective kinase inhibitors that preferentially target the Eph receptor family or subsets of Eph receptors. Strategies that could also be explored include targeting additional Eph receptor interfaces and the ephrin ligands.

Topics: Animals; Humans; Lithocholic Acid; Molecular Targeted Therapy; Neoplasms; Peptides; Protein Kinase Inhibitors; Receptors, Eph Family; Salicylates

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. It is activated, by a mechanism requiring the tumor suppressor LKB1, by metabolic stresses that increase cellular ADP:ATP and/or AMP:ATP ratios. Once activated, it switches on catabolic pathways that generate ATP, while switching off biosynthetic pathways and cell-cycle progress. These effects suggest that AMPK activators might be useful for treatment and/or prevention of type 2 diabetes and cancer. Indeed, AMPK is activated by the drugs metformin and salicylate, the latter being the major breakdown product of aspirin. Metformin is widely used to treat diabetes, while there is epidemiological evidence that both metformin and aspirin provide protection against cancer. We review the mechanisms of AMPK activation by these and other drugs, and by natural products derived from traditional herbal medicines.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Anti-Bacterial Agents; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Neoplasms; Protein Serine-Threonine Kinases; Salicylates

The Ras family of genes is involved in the cellular regulation of proliferation, differentiation, cell adhesion and apoptosis. The K-ras gene is mutated in over 90% of pancreatic cancer cases. Salirasib (S-trans,trans-farnesylthiosalycilic acid [FTS]) is a synthetic small molecule that acts as a potent Ras inhibitor. It is a farnesylcysteine mimetic that selectively disrupts the association of active RAS proteins with the plasma membrane. Animal studies demonstrated that salirasib inhibited tumor growth, downregulated gene expression in the cell cycle and Ras signaling pathways. In a clinical study of salirasib combined with standard doses of gemcitabine, it was demonstrated that the two drugs have no overlapping pharmacokinetics. The salirasib recommended dose was 600 mg twice daily and the progression-free survival was 4.7 months. Future studies will determine whether salirasib adds to the anti-tumor activity of drugs approved by the US FDA for pancreatic cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Membrane; Clinical Trials, Phase I as Topic; Deoxycytidine; Disease-Free Survival; Drug Screening Assays, Antitumor; Farnesol; Farnesyltranstransferase; Galectins; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Middle Aged; Neoplasm Proteins; Neoplasms; Pancreatic Neoplasms; Protein Binding; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Salicylates; Signal Transduction

NF-kappaB activity is elevated in a high proportion of cancers, particularly advanced cancers that have been treated previously. Cytotoxic treatment selects for such up-regulation inasmuch as NF-kappaB promotes transcription of a large number of proteins that inhibit both the intrinsic and extrinsic pathways of apoptosis; NF-kappaB also boosts expression of mdr1, which expels many drugs from cells. Indeed, high NF-kappaB activity appears to be largely responsible for the chemo- and radioresistance of many cancers. Thus, agents that suppress NF-kappaB activity should be useful as adjuvants to cytotoxic cancer therapy. Of the compounds that are known to be NF-kappaB antagonists, the most practical for current use may be the nonsteroidal anti-inflammatory drugs aspirin, salicylic acid, and sulindac, each of which binds to and inhibits Ikappa kinase- beta, a central mediator of NF-kappa activation; the low millimolar plasma concentrations of salicylate required for effective inhibition of this kinase in vivo can be achieved with high-dose regimens traditionally used to manage rheumatic disorders. The gastrointestinal toxicity of such regimens could be minimized by using salsalate or enteric-coated sodium salicy-late or by administering misoprostol in conjunction with aspirin therapy. Presumably, best results would be seen if these agents were administered for several days prior to a course of chemo- or radiotherapy, continuing throughout the course. This concept should first be tested in nude mice bearing xenografts of chemoresistant human tumors known to have elevated NF-kappa activity. Ultimately, more complex adjuvant regimens can be envisioned in which salicylates are used in conjunction with other NF-kappa antagonists and/or agents that target other mediators of down-regulated apoptosis in cancer, such as Stat3; coadministration of salicylate and organic selenium may have intriguing potential in this regard. These strategies may also have potential as adjuvants to metronomic chemotherapy, which seeks to suppress angio-genesis by targeting cycling endothelial cells in tumors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Humans; Mice; Neoadjuvant Therapy; Neoplasms; NF-kappa B; Salicylates

As RAS oncoproteins play a major role in human malignancy, inhibiting RAS function is a promising approach for developing anticancer therapies. Among these approaches are agents such as farnesyltransferase inhibitors (FTIs) and the nontoxic farnesylcysteine analogue farnesylthiosalicylic acid (FTS) that dislodges all RAS isoforms from the membrane, as well as methods to restore regulation of RAS-GTP levels and to alter the interaction of RAS-GTP with downstream targets.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Drug Design; Enzyme Inhibitors; Farnesol; Farnesyltranstransferase; Humans; Neoplasms; ras Proteins; Salicylates

Topics: Acetates; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Humans; Neoplasms; Opium; Pain Management; Palliative Care; Propionates; Salicylates

Topics: Acidosis; Bicarbonates; Biguanides; Diabetes Mellitus; Epilepsy; Ethanol; Fructose; Heart Failure; Humans; Hypoglycemic Agents; Lactates; Leukocytosis; Methanol; Neoplasms; Physical Exertion; Salicylates; Shock

The roles of changes in cellular redox, interorgan lactate flux and balance, and quantitative aspects of lactate metabolism in the pathogenesis of lactic acidosis are discussed. Altered metabolism of pyruvate is central to the development of lactic acidosis and hyperlactatemia. Lactic acidosis occurs as a result of a relative or absolute imbalance in lactate production and utilization. Lactate utilization for oxidative purposes and for the resynthesis of glucose is essential for the maintenance of acid-base balance. Because of its role in lactate homeostasis the liver may play a central role in acid-base balance. Impairment of hepatic utilization of lactate may produce lactic acidosis.

Topics: Acidosis; Animals; Diabetic Ketoacidosis; Dichloroacetic Acid; Ethanol; Homeostasis; Humans; Hypoglycemia; Kidney; Lactates; Liver; Liver Diseases; Neoplasms; Phenformin; Renal Dialysis; Salicylates; Seizures; Vasodilator Agents

Topics: Analgesics; Arthritis, Rheumatoid; Aspirin; Headache; Humans; Ischemia; Kinetics; Neoplasms; Neuralgia; Phenacetin; Phenylbutazone; Salicylates; Time Factors; Wounds and Injuries

Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy.. Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen.. A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. C. Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation.. JAPIC Clinical Trials Information; JapicCTI-121751.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesol; Female; Humans; Male; Middle Aged; Neoplasm Staging; Neoplasms; ras Proteins; Salicylates

This phase I first-in-human trial evaluated salirasib, an S-prenyl derivative of thiosalicylic acid that competitively blocks RAS signaling.. Patients with advanced cancers received salirasib twice daily for 21 days every 4 weeks. Doses were escalated from 100 to 200, 400, 600, and 800 mg.. The most common toxicity was dose-related diarrhea (Grade 1-2, 79% of 24 patients). Other toxicities included abdominal pain, nausea, and vomiting. No Grade 3-4 toxicity was noted. Nineteen (79%) patients had no drug-related toxicity >Grade 1. Dose-limiting toxicity (DLT) was not reached, but all three patients treated with 800 mg experienced Grade 1-2 diarrhea, brogating dose escalation. Six patients were treated at a dose of 600 mg with no DLTs. Seven (29%) patients had stable disease on salirasib for ≥4 months (range 4-23+). The salirasib pharmacokinetic profile was characterized by slow absorption and a rapid elimination phase following oral administration. Salirasib exposure (C(max); day 1 AUC(inf) vs. day 15 AUC(0-12 h)) was similar between days 1 and 15 (P > 0.05). The T(1/2) (mean ± SD) was 3.6 ± 2.2 h on day 1.. Salirasib therapy was well tolerated. The recommended dose for phase II studies is 600 mg twice daily.

Topics: Adult; Aged; Antineoplastic Agents; Farnesol; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasms; Salicylates; Stereoisomerism

Topics: Adult; Aged; Clinical Trials as Topic; Diflunisal; Female; Humans; Male; Middle Aged; Neoplasms; Pain, Intractable; Salicylates

Topics: Binding Sites; Cajanus; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Models, Molecular; Molecular Docking Simulation; Neoplasms; Protein Binding; Protein Conformation; Protein Kinases; Protein Serine-Threonine Kinases; Salicylates; Stilbenes; Survival Analysis

Topics: Artificial Cells; Caco-2 Cells; Carcinoembryonic Antigen; Humans; Neoplasms; Salicylates; Synthetic Biology

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Flavonoids; Humans; Molecular Docking Simulation; Neoplasms; Salicylates; Tubulin

To investigate the relative risk of cancer development in rheumatoid arthritis (RA) patients in Greece after taking into consideration treatment modalities. The present analysis used data on the medical history of 26 331 participants in the Greek arm of the European Prospective Investigation into Cancer and Nutrition that were collected at enrollment and thereafter during active follow-up. A history of RA and of drug treatment for the disease, as reported at baseline examination, was linked to cases of cancer reported during follow-up. A total of 91 (9.9%) patients with RA developed a cancer compared with 1542 (6.1%) patients without RA. The overall hazard ratios of all cancers increased 25% [95% confidence interval (CI): 1-54] among participants with prevalent RA, and almost all the site-specific incident cancer sites considered had rate ratios above unity. In terms of the contribution of RA medication, the hazard ratios of patients treated with salicylates was close to unity (1.07, 95% CI: 0.69-1.65), whereas those who were not treated with salicylates had a 31% (95% CI: 3-67) increased risk for cancer incidence compared with those without RA at baseline. RA patients have excess cancer risk because of either underlying complex disease pathways or treatment agents targeting immune function. Administration of salicylates appears to reduce the risk of developing malignancies.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Carcinogenesis; Cyclooxygenase Inhibitors; Female; Follow-Up Studies; Greece; Humans; Incidence; Male; Middle Aged; Neoplasms; Prevalence; Proportional Hazards Models; Prospective Studies; Risk Factors; Salicylates; Young Adult

We report on our preclinical findings of a simple salicylic diamine compound (THG 1213) which has yielded exceptional results as a potential chemotherapeutic drug. THG 1213 is an easy to synthesize chiral and metal-free salan compound.. THG 1213 was tested on several leukemia, lymphoma and solid tumor cell lines in vitro. The effects have been studied by LDH release essay, FACS flow cytometry, photometric cell count, immunoblotting, and NMR spectroscopy.. THG 1213 selectively inhibits proliferation and induces apoptosis in leukemia, lymphoma and solid tumor cell lines. Necrosis or effects on healthy leucocytes could not be detected. Apoptosis is induced via the intrinsic and extrinsic pathways. The salan THG 1213 overcomes multidrug resistance in tumor cells and acts synergistically with vincristine and daunorubicin.. THG 1213 displays remarkable antitumor properties. In particular, the lack of metallic components of THG 1213 could prove to be beneficial in future clinical trials, as metal-containing drugs are known to show severe side effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Daunorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; Leukemia; Lymphoma; Neoplasms; Phenylenediamines; Salicylates; Vincristine

MUC1 is a transmembrane mucin that can promote cancer progression, and its upregulation correlates with a worse prognosis in colon cancer. We examined the effects of overexpression of MUC1 in colon cancer cells, finding that it induced epithelial to mesenchymal transition (EMT), including enhanced migration and invasion, and increased Akt phosphorylation. When the clones were treated with the aspirin metabolite salicylate, Akt phosphorylation was decreased and EMT inhibited. As the salicylate motif is necessary for the activity of the lysine acetyltransferase (KAT) inhibitor anacardic acid, we hypothesized these effects were associated with the inhibition of KAT activity. This was supported by anacardic acid treatment producing the same effect on EMT. In vitro KAT assays confirmed that salicylate directly inhibited PCAF/Kat2b, Tip60/Kat5 and hMOF/Kat8, and this inhibition was likely involved in the reversal of EMT in the metastatic prostate cancer cell line PC-3. Salicylate treatment also inhibited EMT induced by cytokines, illustrating the general effect it had on this process. The inhibition of both EMT and KATs by salicylate presents a little explored activity that could explain some of the anti-cancer effects of aspirin.

Topics: Anacardic Acids; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Lysine Acetyltransferases; Male; Mucin-1; Neoplasms; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Salicylates

Searching for prospective vanadium-based drugs for cancer treatment, a new series of structurally related [V

Topics: Antineoplastic Agents; Cell Death; Cell Membrane; Cisplatin; Cytotoxins; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; MCF-7 Cells; Neoplasms; Salicylates; Schiff Bases; Vanadates

Epidemiological studies have demonstrated a significant correlation between regular aspirin use and reduced colon cancer incidence and mortality; however, the pathways by which it exerts its anti-cancer effects are still not fully explored. We hypothesized that aspirin's anti-cancer effect may occur through downregulation of c-Myc gene expression. Here, we demonstrate that aspirin and its primary metabolite, salicylic acid, decrease the c-Myc protein levels in human HCT-116 colon and in few other cancer cell lines. In total cell lysates, both drugs decreased the levels of c-Myc in a concentration-dependent fashion. Greater inhibition was observed in the nucleus than the cytoplasm, and immunofluorescence studies confirmed these observations. Pretreatment of cells with lactacystin, a proteasome inhibitor, partially prevented the downregulatory effect of both aspirin and salicylic acid, suggesting that 26S proteasomal pathway is involved. Both drugs failed to decrease exogenously expressed DDK-tagged c-Myc protein levels; however, under the same conditions, the endogenous c-Myc protein levels were downregulated. Northern blot analysis showed that both drugs caused a decrease in c-Myc mRNA levels in a concentration-dependent fashion. High-performance liquid chromatography (HPLC) analysis showed that aspirin taken up by cells was rapidly metabolized to salicylic acid, suggesting that aspirin's inhibitory effect on c-Myc may occur through formation of salicylic acid. Our result suggests that salicylic acid regulates c-Myc level at both transcriptional and post-transcription levels. Inhibition of c-Myc may represent an important pathway by which aspirin exerts its anti-cancer effect and decrease the occurrence of cancer in epithelial tissues.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blotting, Northern; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Chemoprevention; Chromatography, High Pressure Liquid; Down-Regulation; Fluorescent Antibody Technique; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Proto-Oncogene Proteins c-myc; Salicylates

Novel series of Farnesylthiosalicylic acid-diamine/phenylpropenoic acid hybrids were designed and synthesized. Their in vitro growth inhibitory assays showed that most compounds displayed strong antiproliferation activity against seven cancer cells. Especially, the new hybrid 12 f, by the conjugation of 10a with ferulic acid, could selectively suppress the proliferation of tumor cells and display significantly lower toxicities to normal cells than its intermediate 10a. Furthermore, 12 f dose-dependently induced SMMC-7721 cell apoptosis. Additionally, our observations demonstrated that 12 f inhibited both Ras-related signaling and phosphorylated NF-κB synergistically, which may be advantageous to the strong antitumor activities of 12 f. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Diamines; Farnesol; Humans; Neoplasms; NF-kappa B; Phenylpropionates; Phosphorylation; ras Proteins; Salicylates; Signal Transduction

A series of iron(II/III) salophen (salph) complexes involving monodentate azole-derived ligands, having the composition [Fe(II)(salph)(HL1)] (1) and [Fe(III)(salph)(L)] (2-6), where HL1=imidazole, L=1,2,4-triazol-1-ido (L2), benzo[d][1,2,3]triazol-1-ido (L3), 5-aminotetrazol-1-ido (L4), 5-phenyltetrazol-1-ido (L5), and 5-methyltetrazol-1-ido (L6) ligand, was prepared and characterized by elemental analyses, infrared, Mössbauer and X-ray photolelectron spectroscopy, magnetic data and electrospray-ionization mass spectrometry. X-ray structure of 1 revealed a distorted square-pyramidal geometry in the vicinity of the iron(II) atom. The complexes were evaluated for their in vitro antitumor activity against the panel of six human cancer cell lines (HOS, MCF7, A549, HeLa, A2780 and G-361) and were found to be highly cytotoxic, showing the best IC50 value of 58nM for [Fe(III)(salph)(L6)] (6) against the ovarian carcinoma A2780 cell line, being 200-times more effective than cisplatin. In vitro cytotoxicity of complexes 1-6 on primary culture of human hepatocytes and calf-thymus DNA (CT-DNA) binding studies using the fluorescence titration were also performed.

Topics: Antineoplastic Agents; Azoles; Drug Screening Assays, Antitumor; Female; HeLa Cells; Hepatocytes; Humans; Iron; Male; MCF-7 Cells; Neoplasms; Salicylates

Inflammation has a critical role in the tumor progression, free radical damage can worse the status of patients in cancer condition. The anti-cancer agents capable of inhibiting inflammation and scavenging free radicals attract a lot of our interest. Aimed at the discovery of such anti-tumor agent, a novel intercalator, benzyl 1-[4-hydroxy-3-(methoxycarbonyl)-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate (BPIC) was presented. The docking investigation of BPIC and doxorubicin towards the DNA (PDB ID: 1NAB) gave equal score and similar feature. The anti-proliferation assay of 8 cancer cells identified S180 cells had equal sensitivity to BPIC and doxorubicin. The anti-tumor assay defined the efficacy of BPIC been 2 folds higher than that of doxorubicin. At 1μmol/kg of dose BPIC effectively inhibited xylene-induced ear edema and decreased the plasma TNF-α and IL-8 of the mice. BPIC scavenged ∙OH, ∙O2(-) and NO free radicals in a concentration dependent manner and NO free radicals had the highest sensitivity. BPIC could be a novel anti-tumor lead capable of simultaneously inhibiting inflammation and scavenging free radicals.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Carbolines; Cell Line, Tumor; Free Radical Scavengers; Free Radicals; Humans; Inflammation; Intercalating Agents; Mice; Molecular Docking Simulation; Neoplasms; Salicylates

Ginkgolic acid (GA) is a botanical drug extracted from the seed coat of Ginkgo biloba L. with a wide range of bioactive properties, including anti-tumor effect. However, whether GA has antitumor effect on pancreatic cancer cells and the underlying mechanisms have yet to be investigated. In this study, we show that GA suppressed the viability of cancer cells but has little toxicity on normal cells, e.g, HUVEC cells. Furthermore, treatment of GA resulted in impaired colony formation, migration, and invasion ability and increased apoptosis of cancer cells. In addition, GA inhibited the de novo lipogenesis of cancer cells through inducing activation of AMP-activated protein kinase (AMPK) signaling and downregulated the expression of key enzymes (e.g. acetyl-CoA carboxylase [ACC], fatty acid synthase [FASN]) involved in lipogenesis. Moreover, the in vivo experiment showed that GA reduced the expression of the key enzymes involved in lipogenesis and restrained the tumor growth. Taken together, our results suggest that GA may serve as a new candidate against tumor growth of pancreatic cancer partially through targeting pathway driving lipogenesis.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Fatty Acid Synthases; Ginkgo biloba; Hep G2 Cells; Human Umbilical Vein Endothelial Cells; Humans; Lipogenesis; Male; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasms; Pancreatic Neoplasms; RNA Interference; Salicylates; Signal Transduction

PPARγ is an essential regulator of lipid, glucose, and insulin metabolism. PPARγ full agonists, such as thiazolidinediones, are the mainstay drugs for the treatment of type 2 diabetes; however, undesirable clinical side effects have contributed to poor compliance with therapy and limited their full therapeutic potential. In the last few years, many efforts have been made in the discovery and development of selective PPARγ modulators (SPPARγMs) as safer alternatives to PPARγ full agonists.. This application claims the plant-derived amorfrutins or their synthetic analogs as SPPARγMs with potential to exhibit glucose-lowering effects without provoking side effects associated with full PPARγ activation. Specifically, the in vivo glucose-lowering properties of the high-affinity SPPARγM amorfrutin B are described. Moreover, examples of this class of compounds exhibit interesting antiproliferative activities.. The patent (WO2014177593 A1) under discussion proposes enriching functional food products or phytomedical extracts with safe licorice extracts, containing sufficient amounts of amorfrutins, with the ultimate goal of inhibiting the early development of disorders such as insulin resistance. Interestingly, some example compounds show anticancer properties in colon, prostate, and breast malignancies. However, further in vivo investigations of the claimed compounds for these specific indications will be necessary to definitively support their clinical applications.

Topics: Animals; Antineoplastic Agents; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Neoplasms; Patents as Topic; PPAR gamma; Salicylates

Fourteen hybrids of farnesylthiosalicylic acid (FTS) with various diamines were synthesized and biologically evaluated. It was found that FTS-monoamide molecules (10a-g) displayed strong anti-proliferative activity against seven human cancer cell lines, superior to FTS and FTS-bisamide compounds (11a-g). The mono-amide 10f was the most active, with IC₅₀s of 3.78-7.63 μM against all tested cancer cells, even more potent than sorafenib (9.12-22.9 μM). In addition, 10f induced SMMC-7721 cell apoptosis, down-regulated the expression of Bcl-2 and up-regulated Bax and caspase-3. Furthermore, 10f had the improved aqueous solubility relative to FTS. Finally, treatment with 10f dose-dependently inhibited the Ras-related signaling pathways in SMMC-7721 cells. Collectively, 10f could be a promising candidate for the intervention of human cancers.

Topics: Antineoplastic Agents; Apoptosis; Farnesol; Humans; Neoplasms; Salicylates; Signal Transduction

Salicylates are among the oldest medicinal compounds known to humans, and have been used to reduce fever, pain, and inflammation. The major oral salicylates are aspirin and salsalate, both of which are rapidly metabolized to salicylate in vivo. Owing to its acetyl group, aspirin irreversibly inhibits cyclo-oxygenases and thus blocks platelet aggregation, whereas salsalate has been used for treatment of inflammatory diseases such as rheumatoid arthritis. Recently, beneficial effects of salicylates in type 2 diabetes and cancer have been proposed. This has led to renewed interest in understanding how these simple molecules have such diverse and multifaceted effects. Here we discuss the idea that AMP-activated protein kinase (AMPK) might mediate some effects of salicylate-based drugs, particularly by modulating cellular metabolism.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Diabetes Mellitus; Enzyme Activation; Humans; Neoplasms; Salicylates

Restenosis (renarrowing of the blood vessel wall) and cancer are two different pathologies that have drawn extensive research attention over the years. Antiproliferative drugs such as paclitaxel inhibit cell proliferation and are therefore effective in the treatment of cancer as well as neointimal hyperplasia, which is known to be the main cause of restenosis. Antiproliferative drugs are highly hydrophobic and their release from porous biodegradable structures is therefore advantageous. The release profiles of four antiproliferative drugs from highly porous polymeric structures were studied in this study in light of the physical properties of both the host polymers and the drug molecules, and a qualitative model was developed. The chemical structure of the polymer chain directly affects the drug release profile through water uptake in the early stages or degradation and erosion in later stages. It also affects the release profile indirectly, through the polymer's 3D porous structure. However, this effect is minor. The drug volume and molecular area dominantly affect its diffusion rate from the 3D porous structure and the drug's solubility parameter compared with that of the host polymer has some effect on the drug release profile. This model can also be used to describe release mechanisms of other hydrophobic drugs from porous structures.

Topics: Antineoplastic Agents; Biocompatible Materials; Drug-Eluting Stents; Farnesol; Humans; Models, Molecular; Neoplasms; Paclitaxel; Polyglactin 910; Porosity; Salicylates; Sirolimus; Solubility

Two novel palladium(II) complexes with a thiosalicylic acid (HSC(6)H(4)CO(2)H) ligand, with the formulas [Pd(TSA)(L)]·mH(2)O (TSA is thiosalicylic acid; in complex 1, L is 1,10-phenanthroline and m = 1; in complex 2, L is 2,2'-bipyridine and m = 2), have been synthesized and characterized. The coordination geometry of both palladium atoms is square planar; they are four-coordinated and each is coordinated in an N,N,O(-),S(-) mode. There is a sigmoid oxygen chain in complex 1, but an oxygen ring in complex 2. The competitive binding of the complexes to HeLa cell DNA (HL-DNA) has been investigated by fluorescence spectroscopy. The results show that the two complexes have the ability to bind with HL-DNA. Viscosity studies suggest that the complexes bind to DNA by intercalation. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the HL-DNA. The two complexes exhibit cytotoxic specificity and a significant cancer cell inhibitory rate. The apoptosis tests indicated that the complexes have an apoptotic effect. Furthermore, complex 1 exhibits more biological activity than complex 2, which is mainly because the area of the aromatic ring of 1,10-phenanthroline is larger than that of 2,2'-bipyridine.

Topics: 2,2'-Dipyridyl; Antineoplastic Agents; Apoptosis; DNA; HeLa Cells; Humans; Intercalating Agents; Ligands; Neoplasms; Palladium; Phenanthrolines; Salicylates; Sulfhydryl Compounds; Sulfur

Dinuclear Cu(II) complexes, [Cu(2) (salophen)(2) ] (1) and [Cu(2) (salen)(2) ] (2), with Schiff bases derived from salicylaldehyde and o-phenylenediamine (ophen) or ethylenediamine (en) were synthesized and characterized. They exhibit square-planar geometry with CuN(2) O(2) coordination, where the dianionic Schiff base acts as a tetradentate N(2) O(2) donor ligand. Calf thymus (CT)-DNA Binding studies revealed that the complexes possess good binding propensities (K(b) =3.13×10(5) for 1 and K(b) =2.99×10(5)  M(-1) for 2). They show good DNA-cleavage abilities under oxidative and hydrolytic conditions. Complex 1 binds and cleaves DNA more efficiently as compared to 2 due to the presence of an extended aromatic phenyl ring which might be involved in an additional stacking interaction with DNA bases. From the kinetic experiments, hydrolytic DNA-cleavage rate constants were determined as 1.54 for 1 and 0.72 h(-1) for 2. The nuclease activities of 1 and 2 are significant, giving rise to (2.03-2.88)×10(7) -fold rate enhancement compared to non-catalyzed DNA cleavage.

Topics: Animals; Antineoplastic Agents; Binding Sites; Cattle; Copper; DNA; DNA Cleavage; Ethylenediamines; Models, Molecular; Neoplasms; Organometallic Compounds; Salicylates; Schiff Bases

Ginkgolic acids (GAs), extracted from the seed coat of Ginkgo biloba L. Our previous study has shown that GA monomer could inhibit the growth of Hep-2 significantly and induce the fragmentation of the chromosomal DNA. To further assess the antitumor potential and turn it into a candidate new antitumor drug, the antitumor mechanism of GA was investigated.. The cytotoxicity and antitumor effect of GA monomer were assayed by MTT colorimetric assay with nontumorogenic MC-3T3-E1 as well as tumorogenic Hep-2 and Tac8113 cell lines. The effect of GA monomer on the proliferation of tumor cell lines was analyzed with MTT colorimetric and CFSE labeled assay. Cell cycle distribution and measurement of the percentage of apoptotic cells were performed by flow cytometry following stained with propidium iodide, annexin V-FITC. The expression of apoptotic proteins Bcl-2, Bax and caspase-3 was analyzed with Western blot.. GA only inhibited the growth of tumorogenic cell lines in a both dose- and time-dependent manner. Tumor cells were treated with GA for 72 h, 70.53 ± 4.54% Hep-2 and 63.5 ± 7.2% Tca8113 cells were retarded at GO/G1 phase, and the percentage of apoptosis was 40.4 ± 1.58 and 38.4 ± 1.7%, respectively. GA-treated activated caspase-3 downregulated the expression of anti-apoptotic Bcl-2 protein and upregulated the expression of pro-apoptotic Bax protein, eventually leading to a decrease in the Bcl-2/Bax ratio in tumor cells.. The antitumor action of GA was due to inhibiting the proliferation in a manner of inhibiting division, retarding the progress of cell cycle and inducing apoptosis, making GA a candidate as new antitumor drug.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Line, Tumor; Colorimetry; Flow Cytometry; G1 Phase; Humans; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Resting Phase, Cell Cycle; Salicylates

Lecanoric acid (1), orsellinic acid methyl ester (2), orcinol (3), and usnic acid (4) were isolated from the lichen Parmelia subrudecta, collected on Palma of the Canary Islands, Spain. Compounds 1, 2, 3, and 4 were purified by solvent extraction, silica gel column chromatography, and preparative high-performance liquid chromatography (HPLC) consecutively. The structures of the four compounds were elucidated by one- and two-dimensional nuclear magnetic resonance (NMR) experiments and mass spectrometric investigations. These compounds showed activity against important gram-positive and gram-negative pathogens like mycobacteria and multiresistant staphylococci. This activity is combined with antiproliferative activity and cytotoxicity.

Topics: Anti-Infective Agents; Antineoplastic Agents; Bacteria; Bacterial Infections; Benzofurans; Cell Line, Tumor; Cell Proliferation; Humans; Lichens; Magnetic Resonance Spectroscopy; Molecular Structure; Neoplasms; Resorcinols; Salicylates; Spectrometry, Mass, Electrospray Ionization

The Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS, Salirasib) interferes with Ras membrane interactions that are crucial for Ras-dependent transformation. It remains unknown whether modifications of the carboxyl group of FTS can affect its activity. Here we show that specific modifications of the FTS carboxyl group by esterification or amidation yield compounds with improved growth inhibitory activity, compared to FTS, as shown in Panc-1 and U87 cells. The most potent compounds were FTS-methoxymethyl ester and FTS-amide. However, selectivity toward active Ras-GTP, as known for FTS, was apparent with the amide derivatives of FTS. FTS-amide exhibited the overall highest efficacy in inhibition of Ras-GTP and cell growth. This new compound significantly inhibited growth of both Panc-1 tumors and U87 brain tumors. Thus amide derivatives of the FTS carboxyl group provide potent cell-growth inhibitors without loss of selectivity toward the active Ras protein and may serve as new candidates in cancer therapy.

Topics: Amides; Animals; Antineoplastic Agents; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Farnesol; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Molecular Structure; Neoplasms; Oncogene Protein p21(ras); Salicylates; Xenograft Model Antitumor Assays

Five compounds representative of major structural classes of lichen polyketides, VIZ. (+)-usnic (1), salazinic (2), vulpinic (3), gyrophoric (4), and evernic acids (5), were investigated for their ability to affect cell proliferation or wound healing, two functional targets of relevance for research on cancer or tissue regeneration. The experiments were carried out on MM98 malignant mesothelioma cells, A431 vulvar carcinoma cells, and HaCaT keratinocytes. The NRU and CV cytotoxicity assays showed high toxicity for (+)-usnic acid, intermediate toxicity for vulpinic acid, and low toxicity for salazinic, gyrophoric and evernic acids. Scratch wounding experiments on HaCaT monolayers, in the presence of subtoxic doses of lichen compounds, showed strong wound closure effects by (+)-usnic and gyrophoric acid, an intermediate effect by vulpinic and salazinic acids, and no effect by evernic acid. A combination of (+)-usnic and gyrophoric acids gave a further increase in the wound closure rates. The results of a cell migration test correlated with the wound healing data. In conclusion, (+)-usnic acid might be a particularly interesting compound for the prevention of hyperproliferation syndromes, while (+)-usnic and gyrophoric acids qualify as interesting leads in the promotion of tissue regeneration.

Topics: Antineoplastic Agents, Phytogenic; Benzoates; Benzofurans; Cell Line, Tumor; Cell Proliferation; Female; Furans; Humans; Hydroxybenzoates; Keratinocytes; Lactones; Lichens; Neoplasms; Phenylacetates; Phytotherapy; Plant Extracts; Salicylates; Wound Healing

Chronic activation of Ras proteins by mutational activation or by growth factor stimulation is a common occurrence in many human cancers and was shown to induce and be required for tumor growth. Even if additional genetic defects are present, "correction" of the Ras defect has been shown to reverse Ras-dependent tumorigenesis. One way to block Ras protein activity is by interfering with their spatiotemporal localization in cellular membranes or in membrane microdomains, a prerequisite for Ras signaling and biological activity. Detailed reports describe the use of this method in studies employing farnesylthiosalicylic acid (FTS, Salirasib), a Ras farnesylcysteine mimetic, which selectively disrupts the association of chronically active Ras proteins with the plasma membrane. FTS competes with Ras for binding to Ras-escort proteins, which possess putative farnesyl-binding domains and interact only with the activated form of Ras proteins, thereby promoting Ras nanoclusterization in the plasma membrane and robust signals. This chapter presents three-dimensional time-lapse images that track the FTS-induced inhibition of membrane-activated Ras in live cells on a real-time scale. It also describes a mechanistic model that explains FTS selectivity toward activated Ras. Selective blocking of activated Ras proteins results in the inhibition of Ras transformation in vitro and in animal models, with no accompanying toxicity. Phase I clinical trials have demonstrated a safe profile for oral FTS, with minimal side effects and promising activity in hematological malignancies. Salirasib is currently undergoing trials in patients with pancreatic cancer and with nonsmall cell lung cancer, with or without identified K-Ras mutations. The findings might indicate whether with the disruption of the spatiotemporal localization of oncogenic Ras proteins and the targeting of prenyl-binding domains by anticancer drugs is worth developing as a means of cancer treatment.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Cells, Cultured; Farnesol; Humans; Mice; Neoplasms; ras Proteins; Salicylates; Signal Transduction

Deregulation of Ras pathways results in complex abnormalities of multiple signaling cascades that contribute to human malignancies. Ras is therefore considered an appropriate target for cancer therapy. In light of the complexity of the deregulated Ras pathway, it is important to decipher at the molecular level the response of cancer cells to Ras inhibitors that would reregulate it. In the present study, we used gene expression profiling as a robust method for the global dissection of gene expression alterations that resulted from treatment with the Ras inhibitor S-farnesylthiosalicylic acid (FTS; salirasib). Use of a ranking-based procedure, combined with functional analysis and promoter sequence analysis, enabled us to decipher the common and most prominent patterns of the transcriptional response of five different human cancer cell lines to FTS. Remarkably, the analysis identified a distinctive core transcriptional response to FTS that was common to all cancer cell lines tested. This signature fits well to a recently described deregulated Ras pathway signature that predicted sensitivity to FTS. Taken together, these studies provide strong support for the conclusion that FTS specifically reregulates defective Ras pathways in human tumor cells. Ras pathway reregulation by FTS was manifested by repression of E2F-regulated and NF-Y-regulated genes and of the transcription factor FOS (all of which control cell proliferation), repression of survivin expression (which blocks apoptosis), and induction of activating transcription factor-regulated and Bach2-regulated genes (which participate in translation and stress responses). Our results suggest that cancer patients with deregulated Ras pathway tumors might benefit from FTS treatment.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cluster Analysis; Down-Regulation; Farnesol; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Promoter Regions, Genetic; ras Proteins; Salicylates; Transcription, Genetic; Up-Regulation

Simple water-soluble lanthanum and europium complexes are effective at detecting neutral sugars as well as glycolipids and phospholipids. In solutions at physiologically relevant pH the fluorescent lanthanum complex binds neutral sugars with apparent binding constants comparable to those of arylboronic acids. Interference from commonly occurring anions is minimal. The europium complex detects sialic acid-containing gangliosides at pH 7.0 over an asialoganglioside. This selectivity is attributed, in large part, to the cooperative complexation of the oligosaccharide and sialic acid residues to the metal center, based on analogous prior studies. In MeOH, lysophosphatidic acid (LPA), a biomarker for several pathological conditions including ovarian cancer, is selectively detected by the europium complex. LPA is also detected via a fluorescence increase in human plasma samples. The 2-sn-OH moiety of LPA plays a key role in promoting binding to the metal center. Other molecules found in common brain ganglioside and phospholipid extracts do not interfere in the ganglioside or LPA fluorescence assays.

Topics: Biomarkers, Tumor; Carbohydrate Sequence; Europium; Female; Fluorescent Dyes; Gangliosides; Humans; Hydrogen-Ion Concentration; Lanthanum; Lysophospholipids; Methanol; Molecular Sequence Data; Neoplasms; Ovarian Neoplasms; Salicylates

Topics: Anticarcinogenic Agents; Child; Dietary Supplements; Humans; Models, Biological; Neoplasms; Risk Factors; Salicylates

Aspirin (acetylsalicylate) is an inexpensive drug that is used extensively to reduce cardiovascular disease risk. Emerging evidence suggests that aspirin reduces the risk of other chronic diseases such as certain forms of cancer. Salicylate may contribute to the disease reduction effects. It is present naturally in fruits and vegetables and individuals with a low intake of these foods may be 'salicylate deficient'. This deleterious state may constitute a significant public health threat. Interventions to prevent deficiency, such as low-dose aspirin programmes, could have substantial beneficial health impacts around the world.

Topics: Alzheimer Disease; Aspirin; Cardiovascular Diseases; Chronic Disease; Fruit; Humans; Neoplasms; Public Health; Salicylates; Vegetables

As part of our screening program for cancer inhibitory agents effective specifically in the promotion stage of cancer development, we have evaluated the possible inhibitory effects of 36 non-steroidal anti-inflammatory drugs (NSAIDs) on the Epstein-Barr virus early antigen (EBV-EA) activation which was induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. All the drugs were observed to inhibit the EBV-EA activation at low doses with low toxicity. The two most active anti-tumor promoting agents were the arylacetic acid derivatives, etodolac and sulindac. We also report for the first time the activities of 14 new NSAIDs belonging to different classes as potential cancer chemopreventive agents. A structure-activity relationship study showed that among the salicylic acid derivative tested, the oxidation of the thiol group to dithiol derivatives results in the reduction of the activity. Introduction of amino group on the salicylic acid molecules also results in the reduction of activity in the EBV-EA assay. The results are of great interest in the development of NSAIDs as cancer chemopreventive agents, which halt cancer progression in multistage carcinogenesis, where successive activities are required to evolve into fully-fledged and metastatic cancer.

Topics: Acetates; Anti-Inflammatory Agents, Non-Steroidal; Antigens, Viral; Benzene; Carcinogens; Carcinoma; Cell Survival; Etodolac; Fluorescent Antibody Technique, Indirect; Humans; Nasopharyngeal Neoplasms; Neoplasms; Oxidation-Reduction; Salicylates; Structure-Activity Relationship; Sulindac; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Salicylate and several structurally analogous compounds enhance merocyanine 540 (MC540)-photosensitized killing of leukemia cells (M. A. Anderson, B. Kalyanaraman, and J. B. Feix, Cancer Res., 53: 806-809, 1993). In this work, we show that salicylic acid enhances the binding of MC540 prior to illumination, as well as the light-stimulated uptake of MC540 by target L1210 murine and K562 human leukemia cells. Acetylsalicylic acid, 2,3- and 2,5-dihydroxybenzoic acids, and sodium benzoate also enhance MC540 uptake. The irradiation dose responses for loss of cell survival and enhanced MC540 uptake are well correlated, both being shifted to earlier time points in the presence of salicylate. Salicylic acid also enhanced photodynamic cell killing of A549 lung carcinoma and NIH:OVCAR-3 ovarian carcinoma cells, two cell types which are relatively resistant to MC540-mediated photosensitization. Cellular uptake of the anionic, potential-sensitive oxonol dye, bis-(1,3-dibutylbarbituric acid)-trimethine oxonol, is also increased by salicylate in a dose-dependent fashion. In contrast, cellular uptake of the cationic cyanine dye, 3,3'-dihexyloxacarbocyanine, is unaffected by salicylate. These studies suggest that increased uptake of MC540 is the basis of salicylate enhancement and that changes in plasma membrane potentials may play a mechanistic role in the potentiation of MC540 binding and cell killing.

Topics: Animals; Benzoates; Benzoic Acid; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Fluorescence; Humans; Leukemia; Leukemia L1210; Mice; Neoplasms; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; Salicylates; Salicylic Acid

Both the capacity of healthy human, cancer patient, and mouse plasma proteins to bind flavone acetic acid (FAA) and the qualitative differences in the plasma protein-binding site were studied. The binding capacity of plasma proteins for FAA was saturated within the therapeutic range in both species. The binding of FAA to plasma protein was significantly greater in both healthy human and cancer patient plasma than in mouse plasma. Plasma from patients with cancer bound on the average less FAA than did healthy patient plasma. The concentration of albumin in the plasma varied between healthy humans, cancer patients, and mice, being 5.3 +/- 0.7, 4.7 +/- 0.8, and 3.9 +/- 0.3 g/100 ml, respectively. The protein binding of FAA was found to be dependent on the plasma albumin concentration, but albumin concentration alone was not adequate for the accurate prediction of the percentage of FAA protein bound. Scatchard plots indicated that healthy human plasma had a greater number of high-affinity binding sites than did mouse plasma. FAA binds at the indolebenzodiazepine binding area on albumin and can be displaced from this site by salicylic acid and clofibric acid, but only at supratherapeutic concentrations. Our results indicate that alterations in plasma albumin could contribute to a variable effect with FAA. Therefore, the influence of serum albumin concentration and the nonlinearity of FAA protein binding should be considered in assessment of the appropriateness of a dose schedule for FAA.

Topics: Animals; Binding Sites; Binding, Competitive; Blood Proteins; Clofibric Acid; Flavonoids; Humans; In Vitro Techniques; Mice; Neoplasms; Protein Binding; Salicylates; Salicylic Acid; Serum Albumin

Topics: Benzenesulfonates; Electrophoresis, Polyacrylamide Gel; Humans; Kidney Diseases; Molecular Weight; Mucoproteins; Neoplasms; Salicylates; Solubility

Topics: Benzenesulfonates; Female; Humans; Male; Mucoproteins; Neoplasms; Reference Values; Salicylates; Solubility

In an open study in patients with tumour-induced pain the analgetic effects of the prostaglandin-inhibiting compound diflunisal and the centrally-acting analgetic tilidine N were compared. A dosage of 1 g diflunisal was found to be equivalent to 50 drops of tilidine N and to be subjectively well-tolerated. In the pain-relieving therapy of tumour patients diflunisal appears to offer a genuine alternative to centrally-acting analgetics.

Topics: Aged; Cyclohexanecarboxylic Acids; Diflunisal; Dose-Response Relationship, Drug; Humans; Male; Neoplasms; Pain; Salicylates; Tilidine

Topics: Bone Neoplasms; Breast Neoplasms; Female; Humans; Leukemia, Myeloid, Acute; Neoplasms; Prostaglandins A; Prostaglandins E; Salicylates

Topics: Codeine; Drug Therapy, Combination; Humans; Hydroxyzine; Morphine; Neoplasms; Palliative Care; Salicylates

Topics: Aminopyrine; Analgesics; Drug Therapy, Combination; Humans; Narcotic Antagonists; Narcotics; Neoplasms; Pain; Palliative Care; Salicylates; Terminal Care; Time Factors

Topics: Alcoholic Beverages; Anticoagulants; Blood Transfusion; Cortisone; Drug Therapy, Combination; Gastrointestinal Hemorrhage; Hip Joint; Humans; Indomethacin; Joint Diseases; Kidney Diseases; Liver Cirrhosis; Neoplasms; Phenylbutazone; Postoperative Complications; Prospective Studies; Salicylates; Stomach Diseases

Topics: Allopurinol; Amino Acids; Aspirin; Autoanalysis; Creatinine; Glycosuria; Humans; Kidney Diseases; Neoplasms; Phosphates; Porphobilinogen; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Salicylates; Uric Acid; Xanthine Oxidase

Topics: Adult; Alcoholism; Female; Humans; Liver Diseases; Male; Middle Aged; Neoplasms; Salicylates; Uric Acid

Topics: Arthritis; Cartilage; Chemical Phenomena; Chemistry; Contact Inhibition; Crystallization; DNA; Movement; Muscle Proteins; Muscles; Neoplasms; Proteins; RNA; Salicylates; Surface Properties; Temperature; Transplantation Immunology; Water

Topics: Animals; Bone and Bones; Chromium; Chromium Isotopes; Electrophoresis; Iodine Isotopes; Mice; Neoplasms; Salicylates

Topics: Blood Proteins; Cholesterol; Humans; Lipoproteins; Methods; Neoplasms; Salicylates; Serum Albumin; Serum Globulins

Topics: Blood Chemical Analysis; Blood Proteins; Cellulose; Chromatography, Ion Exchange; Glycoproteins; Humans; Neoplasms; Polarography; Salicylates; Sulfonic Acids

Four patients who had ingested large amounts of phenacetin-salicylate medications were studied during a 12-month period. Renal failure had progressed slowly over a number of years. All patients took the drug because of psychogenic headache. Considerable skill was required to elicit the history of drug habituation. The major features of the nephropathy were multiple episodes of metabolic acidosis, minimal proteinuria, pyuria but no bacteriuria, and polyuria and polydipsia early in the course of drug ingestion. Papillary necrosis was not a prominent clinical feature of this series. Discontinuation of drug ingestion by one patient was associated with recovery of a considerable degree of renal function. Preliminary experimental evidence obtained in the dog suggests that salicylate impaired the efficiency of the counter-current multiplier by decreasing sodium transport in the ascending limb of Henle, and decreased the permeability to water of the distal convoluted and collecting tubule; phenacetin had no such effect.

Topics: Acidosis; Animals; Aspirin; Bacteriuria; Biological Transport; Caffeine; Codeine; Dogs; Drug Therapy; Headache; Humans; Kidney Diseases; Kidney Papillary Necrosis; Kidney Tubules; Metabolism; Neoplasm Recurrence, Local; Neoplasms; Phenacetin; Polyuria; Proteinuria; Pyuria; Salicylates; Sodium; Toxicology

Topics: Ascites; Benzenesulfonates; Blood Proteins; Mucoproteins; Neoplasms; Neoplasms, Experimental; Rats; Research; Salicylates; Salicylic Acid

Topics: Benzenesulfonates; Blood; Blood Proteins; Chromatography; Chromatography, Gel; Hexosamines; Immunoelectrophoresis; Mucoproteins; Neoplasms; Neoplasms, Experimental; Rats; Research; Salicylates; Salicylic Acid

Topics: Benzenesulfonates; Blood Protein Electrophoresis; Blood Proteins; Immunoelectrophoresis; Neoplasms; Proteins; Research; Salicylates; Serum

Topics: Benzenesulfonates; Blood Chemical Analysis; Blood Proteins; Chromatography; Mucoproteins; Neoplasms; Research; Salicylates

Topics: Anemia; Anemia, Hemolytic; Animals; Antineoplastic Agents; Cortisone; Cricetinae; Fibrosarcoma; Neoplasms; Neoplasms, Experimental; Salicylates; Sodium Salicylate

Topics: Antacids; Bismuth; Diagnosis, Differential; Hodgkin Disease; Humans; Neoplasms; Penicillins; Radiography; Salicylates; Stomach; Stomach Neoplasms; Syphilis; Syphilis Serodiagnosis

Topics: Neoplasms; Poliomyelitis; Salicylates