s-trans-trans-farnesylthiosalicylic-acid and Neoplasms

'Epigenetic' regulation of genes via post-translational modulation of proteins is the current mainstay approach for the disease therapies, particularly explored in the Histone Deacetylase (HDAC) class of enzymes. Mainly sight saw in cancer chemotherapeutics, HDAC inhibitors have also found a promising role in other diseases (neurodegenerative disorders, cardiovascular diseases, and viral infections) and successfully entered in various combination therapies (pre-clinical/clinical stages). The prevalent flexibility in the structural design of HDAC inhibitors makes them easily tuneable to merge with other pharmacophore modules for generating multi-targeted single hybrids as a novel tactic to overcome drawbacks of polypharmacy. Herein, we reviewed the putative role of prevalent HDAC hybrids inhibitors in the current and prospective stage as a translational approach to overcome the limitations of the existing conventional drug candidates (parent molecule) when used either alone (drug resistance, solubility issues, adverse side effects, selectivity profile) or in combination (pharmacokinetic interactions, patient compliance) for treating various diseases.

Topics: Animals; Cardiovascular Diseases; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Molecular Targeted Therapy; Neoplasms; Nervous System Diseases

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

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 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

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

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

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

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

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

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

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

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells

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