Novel engineered TRAIL-based chimeric protein strongly inhibits tumor growth and bypasses TRAIL resistance

Targeting of the TRAIL-DR4/5 pathway was proposed as a promising approach for specific induction of apoptosis in cancer cells. Clinical trials, however, showed inadequate efficiency of TRAIL as a monotherapy. It is a widely held view that the application of multifunctional molecules or combination therapy may lead to substantial improvement. Here, we demonstrate the effectiveness and safety of a novel chimeric protein, AD-O51.4, which is a TRAIL equipped with positively charged VEGFA-derived effector peptides. The study was performed in multiple cancer cell line- and patient-derived xenografts. A pharmacokinetic profile was established in monkeys. AD-O51.4 strongly inhibits tumor growth, even leading to complete long-term tumor remission. Neither mice nor monkeys treated with AD-O51.4 demonstrate symptoms of drug toxicity. AD-O51.4 exhibits a satisfactory half-life in plasma and accumulates preferentially in tumors. The cellular mechanism of AD-O51.4 activity involves both cytotoxic effects in tumor cells and antiangiogenic effects on the endothelium. The presence of DRs in cancer cells is crucial for AD-O51.4-driven apoptosis execution. The TRAIL component of the fusion molecule serves as an apoptosis inducer and a cellular anchor for the effector peptides in TRAIL-sensitive and TRAIL-resistant cancer cells, respectively. The FADD-dependent pathway, however, seems to be not indispensable in death signal transduction; thus, AD-O51.4 is capable of bypassing the refractoriness of TRAIL. AD-O51.4-driven cell death, which exceeds TRAIL activity, is achieved due to the N-terminally fused polypeptide, containing VEGFA-derived effector peptides. The high anticancer efficiency of AD-O51.4 combined with its safety has led to the entry of AD-O51.4 into toxicological studies.     

Rho kinase inhibition ameliorates cyclophosphamide-induced cystitis in rats

Naunyn-Schmiedeberg's Archives of Pharmacology - Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CYP). Studies have indicated that Rho kinase (ROCK) inhibitors...     

Adenosine receptor ligands and dizocilpine-induced antinociception in mice

Interactions between adenosine receptor ligands and dizocilpine (uncompetitive NMDA receptor antagonist) was studied in antinociceptive, writhing test in mice. Minimal effective, antinociceptive doses of adenosine receptor agonists were: 0.1 mg/kg (NECA--A1/A2 agonist). Generally, these agonists did not potentiate the subthreshold dose of dizocilpine (0.05 mg/kg). Of all adenosine receptor antagonists used, only caffeine (A2 and A2 antagonists) reversed dizocilpine-induced (0.1 mg/kg) antinociception dose-dependently. These findings indicate that dizocilpin-induced antinociception in the writhing test is only partly influenced by adenosine receptor ligands.     

Influence of adenosine receptor agonists and antagonists on amphetamine-induced stereotypy in rats

The influence of adenosine receptor agonists and antagonists on amphetamine-induced stereotypy was examined in male Wistar rats. Adenosine A2 receptor agonists CGS 21680 (0.5-2 mg/kg ip) and a non-specific A2/A1 receptor agonist NECA (0.05-0.1 mg/kg ip) attenuated in a dose dependent manner amphetamine-induced stereotypy (2 mg/kg sc). CPA as specific agonist of adenosine A1 receptors counteracted this stereotypy, but only in a narrow range of doses (0.1-0.2 mg/kg ip). Adenosine A2A receptor antagonist, DMPX (3 and 6 mg/kg ip) potentiated stereotypy induced by either subthreshold dose of amphetamine 0.5 mg/kg or a high one 2 mg/kg. A non-selective adenosine receptor antagonist, caffeine (10 mg/kg ip) potentiated effect of low dose of amphetamine, but only in a dose of 20 mg/kg ip increased stereotypy induced by 2 mg/kg ip of amphetamine. A selective adenosine A1 receptor antagonist CPT (1 and 3 mg/kg ip) was ineffective in reversing amphetamine-induced stereotypy. These results confirm the existence of adenosine-dopamine interactions in the brain, and the suggestions that A2 adenosine receptor agonists may have antipsychotic properties.     

Influence of sildenafil on the antidepressant activity of bupropion and venlafaxine in the forced swim test in mice

Recent studies highlight the involvement of the nitrergic system in the mechanism of action of antidepressant drugs. Sildenafil, a selective PDE5 inhibitor, was shown to abolish the anti-immobility effects of bupropion, venlafaxine and s-citalopram in mice. In this study we assessed the effects of sildenafil on the activity of bupropion and venlafaxine in the forced swim test in mice. Swim trials were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was evaluated with photoresistor actimeters. Brain and serum concentrations of the studied antidepressants were determined by HPLC method. Sildenafil at a dose of 20 mg/kg, but not 5 and 10 mg/kg, significantly increased the anti-immobility action of bupropion (20 mg/kg). The antidepressant activity of venlafaxine (2 mg/kg) was potentiated by joint administration with sildenafil at doses of 10 and 20 mg/kg. Since the combined treatments did not increase the locomotor activity, the antidepressant-like effects were not related to non-specific behavioral activation. Data from pharmacokinetic studies revealed that sildenafil increased bupropion and venlafaxine levels in serum without affecting their concentrations in the brain. The present study demonstrates the enhancement of anti-immobility action of bupropion and venlafaxine by sildenafil co-administration. The observed changes might have been partly due to pharmacokinetic interactions. However, mechanisms underlying the effects of sildenafil on the antidepressant activity of bupropion and venlafaxine should be carefully evaluated in further studies.     

Investigational NMDA receptor modulators for depression

INTRODUCTION: With regards to depression, the role of N-methyl-D-aspartate receptor (NMDA) was pursued many years ago, mainly in the form of preclinical studies. Since then, there have been several clinical data in the literature indicating the efficacy of NMDA receptor antagonists of either stand-alone or as an adjunct therapy in depression and depression-related diseases. AREAS COVERED: The present review focuses on clinical data of well-known and recently discovered NMDA receptor antagonists/modulators and their mechanisms of action. EXPERT OPINION: Several NMDA receptor modulators have been tested in both human and animal studies to examine their potential antidepressant activity. Most of the compounds that exhibited beneficial properties in the animal tests and models of depression either have never been tested or did not show efficacy in humans. For some of them, such as ketamine, where a consistently reproducible antidepressant effect was found, clinical use is limited by a variety of adverse effects. However, ketamine has become a standard tool for identifying the biological factors associated with rapid antidepressant action and, as such, is a novel target for the development of new therapeutics.     

A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice

Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway.     

Inhibition of the CRF1 receptor influences the activity of antidepressant drugs in the forced swim test in rats

Naunyn-Schmiedeberg's Archives of Pharmacology - Hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) and impairment of the central corticotropin-releasing factor (CRF) system are...