salicylates and Pancreatic-Neoplasms

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

S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA).. In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients' biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination.. Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes.. The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Farnesol; Female; Gemcitabine; Humans; Male; Mice; Mice, Nude; Middle Aged; Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); ras Proteins; Salicylates; Tumor Burden; Xenograft Model Antitumor Assays

A concise synthesis of cajaninstilbene acid was achieved in 7 steps from (E)-3,5-dimethoxystilbene in 8.6% overall yield via the Claisen rearrangement of an aryl reverse-prenyl ether as the key step. Cytotoxic activities against human pancreatic carcinoma PANC-1 cells of cajaninstilbene acid and amorfrutins A-D were also evaluated.

Topics: Cytotoxins; Humans; Pancreatic Neoplasms; Salicylates; Stilbenes

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations. Farnesyl thiosalicylic acid (FTS), also known as salirasib, is a RAS inhibitor that selectively dislodges active RAS proteins from cell membrane, inhibiting downstream signaling. FTS has demonstrated limited therapeutic efficacy in PDAC patients despite being well tolerated.. To improve the efficacy of FTS in PDAC, we performed a genome-wide CRISPR synthetic lethality screen to identify genetic targets that synergize with FTS treatment. Among the top candidates, multiple genes in the endoplasmic reticulum-associated protein degradation (ERAD) pathway were identified. The role of ERAD inhibition in enhancing the therapeutic efficacy of FTS was further investigated in pancreatic cancer cells using pharmaceutical and genetic approaches.. In murine and human PDAC cells, FTS induced unfolded protein response (UPR), which was further augmented upon treatment with a chemical inhibitor of ERAD, Eeyarestatin I (EerI). Combined treatment with FTS and EerI significantly upregulated the expression of UPR marker genes and induced apoptosis in pancreatic cancer cells. Furthermore, CRISPR-based genetic ablation of the key ERAD components, HRD1 and SEL1L, sensitized PDAC cells to FTS treatment.. Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; CRISPR-Cas Systems; Drug Screening Assays, Antitumor; Endoplasmic Reticulum-Associated Degradation; Farnesol; Gene Knockout Techniques; Humans; Hydrazones; Hydroxyurea; Mice; Pancreatic Neoplasms; Proteins; Salicylates; Synthetic Lethal Mutations; Ubiquitin-Protein Ligases; Unfolded Protein Response

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caspase 3; Celecoxib; Cell Line, Tumor; Cell Proliferation; Cell Survival; Farnesol; Gene Expression Regulation, Neoplastic; Humans; NF-kappa B; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Salicylates; Signal Transduction

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

The Ras inhibitor S-trans-trans farnesylthiosalicylic acid (FTS) inhibits active Ras, which controls cell proliferation, differentiation, survival, and metabolism. FTS also inhibits HIF1α expression in cancer cells, leading to an energy crisis. The synthetic glucose analog 2-deoxy-D-glucose (2-DG), which inhibits glycolysis, is selectively directed to tumor cells that exhibit increased glucose consumption. The 2-DG enters tumor cells, where it competes with glucose for glycolytic enzymes. In cancer models, as well as in human phase 1 trials, 2-DG inhibits tumor growth without toxicity. We postulated that under normoxic conditions, tumor cells treated with FTS would be more sensitive than normal cells to 2-DG. We show here that combined treatment with FTS and 2-DG inhibited cancer cell proliferation additively, yet induced apoptotic cell death synergistically both in vitro and in vivo. The induced apoptosis was inferred from QVD-OPH inhibition, an increase in cleaved caspase 3, and loss of survivin. FTS and 2-DG when combined, but not separately, also induced an increase in fibrosis of the tumor tissue, chronic inflammation, and tumor shrinkage. Overall, these results suggest a possible new treatment of pancreatic tumors by the combined administration of FTS and 2-DG, which together induce pancreatic tumor cell death and tumor shrinkage under non-toxic conditions.

Topics: Animals; Antineoplastic Agents; Cell Death; Cell Proliferation; Deoxyglucose; Drug Synergism; Farnesol; Glycolysis; Humans; Mice; Mice, Nude; Organ Size; Pancreas; Pancreatic Neoplasms; Salicylates; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

S-trans,trans-farnesylthiosalicylic acid (salirasib, FTS) is a synthetic small molecule that acts as a potent Ras inhibitor. Salirasib inhibits specifically both oncogenically activated Ras and growth factor receptor-mediated Ras activation, resulting in the inhibition of Ras-dependent tumor growth. The objectives of this study were to develop a sensitive LC-MS/MS assay for determination of FTS in plasma, to assess the bioavailabilty of FTS after oral administration to mice, and then to examine the efficacy of orally administered FTS for inhibition of tumor growth in a nude mouse model.. FTS was isolated from mouse plasma by liquid chromatography on a Columbus 5-mum particle size, 50 x 2 mm id column with a methanol/5 mM ammonium acetate (80/20) mobile phase (isocratic elution) at a flow rate of 0.3 ml/min. MS/MS was performed on a PE Sciex API 365 with Turbo Ion Spray as interface and negative ion ionization; parent ion (m/z): 357.2; daughter ion (m/z) 153.2; retention time 2.3 min. For plasma analysis, the amount of analyte in each sample was calculated by comparing response of the analyte in that sample to a nine-point standard curve linear over the range 3-1000 ng/ml. Pharmacokinetic studies were performed in mice following intraperitoneal dosing (20 mk/kg in PBS) or oral dosing (40 mg/kg in either 0.5% aqueous CMC or corn oil). Panc-1 tumor growth in nude mice was determined following daily oral dosing with FTS in 0.5% CMC (40, 60, or 80 mg/kg), or in combination with weekly gemcitabine (30 mg/kg).. Salirasib was readily detected in mouse plasma by LC-MS/MS at a detection limit of 3 ng/ml. For each route of administration, t (max) was 1 h and t (1/2) ranged from 1.86 to 2.66 h. Compared to IP administration, the oral bioavailabilty of FTS was 69.5% for oral CMC and 55% for oral corn oil suspensions, while clearance and volume of distribution were higher in both oral preparations. The orally administered salirasib inhibited panc-1 tumor growth in a dose dependent manner (67% reduction in tumor weight at the highest dose, P < 0.002 vs. control, n = 10 mice per group) and at a 40 mg/kg daily dose was synergistic with gemcitabine (83% increase in survival rate, n = 8 mice per group).. Salirasib exhibits good bioavailabilty after oral administration, as determined by a highly sensitive method for quantification in plasma. The orally available Ras inhibitor salirasib inhibited growth in nude mice, and may thus be considered for clinical trials.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Chromatography, Liquid; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Farnesol; Gemcitabine; Injections, Intraperitoneal; Mice; Mice, Nude; Pancreatic Neoplasms; Random Allocation; ras Proteins; Salicylates; Solvents; Survival Rate; Tandem Mass Spectrometry

Although non steroidal antiinflammatory drugs (NSAIDs) have been shown to be effective as chemopreventive agents, important side-effects limit their clinical use. A promising novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), has been found to be more active than classical NSAIDs. This study explored the effect of the NO-donating aspirin derivative, NCX 4040, on three human pancreatic adenocarcinoma cell lines (Capan-2, MIA PaCa-2 and T3M4). NCX 4040 activity was compared with that of NCX 4016 (an NO(2)-positional isomer of NCX 4040), SNAP (a standard NO-releasing molecule), NCX 4042 (denitrated analog of NCX 4040), and aspirin. NCX 4040 showed a striking cytocidal activity in all cell lines, already inducing significant percentages of apoptotic cells at 10 muM in Capan-2 cell lines. This study focused on the biological mechanisms of sensitivity and resistance to NCX 4040, highlighting that the cytotoxic action of this drug may be due to the hyperexpression of Bax, its translocation to the mitochondria, the release of Cytochrome C, and the activation of caspases-9 and -3, overall in a p53-independent manner. Moreover, the use of a specific COX-2 inhibitor (NS 398) in the experimental models showed that COX-2 hyperexpression could partially explain the resistance mechanisms to NCX 4040.

Topics: Adenocarcinoma; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Aspirin; Caspase 9; Cell Cycle; Cell Line, Tumor; Cytotoxins; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Nitric Oxide Donors; Nitro Compounds; Pancreatic Neoplasms; S-Nitroso-N-Acetylpenicillamine; Salicylates

Constitutively active Ras proteins, their regulatory components, and overexpressed tyrosine kinase receptors that activate Ras, are frequently associated with cell transformation in human tumors. This suggests that functional Ras antagonists may have anti-tumor activity. Studies in rodent fibroblasts have shown that S-trans, transfarnesylthiosalicylic acid (FTS) acts as a rather specific nontoxic Ras antagonist, dislodging Ras from its membrane anchorage domains and accelerating its degradation. FTS is not a farnesyltransferase inhibitor, and does not affect Ras maturation. Here we demonstrate that FTS also acts as a functional Ras antagonist in human pancreatic cell lines that express activated K-Ras (Panc-1 and MiaPaCa-2). In Panc-1 cells, FTS at a concentration of 25-100 microM reduced the amount of Ras in a dose-dependent manner and interfered with serum-dependent and epidermal growth factor-stimulated ERK activation, thus inhibiting both anchorage-dependent and anchorage-independent growth of Panc-1 cells in vitro. FTS also inhibited tumor growth in Panc-1 xenografted nude mice, apparently without systemic toxicity. Daily FTS treatment (5 mg/kg intraperitoneally) in mice with tumors (mean volume 0.07 cm3) markedly decreased tumor growth (after treatment for 18 days, tumor volume had increased by only 23+/-30-fold in the FTS-treated group and by 127+/-66-fold in controls). These findings suggest that FTS represents a new class of functional Ras antagonists with potential therapeutic value.

Topics: Animals; Antineoplastic Agents; Calcium-Calmodulin-Dependent Protein Kinases; Dose-Response Relationship, Drug; Enzyme Activation; Epidermal Growth Factor; Farnesol; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; ras Proteins; Salicylates; Tumor Cells, Cultured

Microscopic colitis is a syndrome consisting of chronic watery diarrhea, a normal or near-normal gross appearance of the colonic lining, and a specific histological picture described as either lymphocytic colitis or collagenous colitis. Since its initial descriptions a quarter of a century ago, microscopic colitis has become a frequent diagnosis in patients with chronic diarrhea. Understanding of the cause and pathogenesis of microscopic colitis remain incomplete, but potentially important clues have been discovered that shed light on predisposing factors. In particular, specific HLA-DQ genotypes may be permissive for the development of microscopic colitis, and suggest a linkage to the pathogenesis of celiac sprue. Although the differential diagnosis of chronic watery diarrhea is broad, the diagnosis of microscopic colitis is straightforward, involving endoscopic inspection of the colonic mucosa and proper pathologic interpretation of biopsy specimens. As the limitations of drugs ordinarily used for other forms of inflammatory bowel disease are being recognized, new approaches, such as the use of bismuth subsalicylate, are being evaluated. The prognosis of patients with microscopic colitis syndrome remains good, and symptomatic improvement can be expected in most patients.

Topics: Adult; Bismuth; Chronic Disease; Colitis; Colonoscopy; Diagnosis, Differential; Diarrhea; Female; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Organometallic Compounds; Pancreatic Neoplasms; Prognosis; Salicylates; Vipoma

Topics: Adrenal Insufficiency; Carbohydrate Metabolism, Inborn Errors; Ethanol; Glycogen Storage Disease; Hormones, Ectopic; Humans; Hypoglycemia; Hypopituitarism; Insulin; Islets of Langerhans; Liver Diseases; Nutrition Disorders; Pancreatic Neoplasms; Salicylates; Sulfonylurea Compounds