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- Pan-Histone Demethylase Inhibitors Simultaneously Targeting Jumonji C and Lysine Specific Demethylases Display High Anticancer Activities. [JOURNAL ARTICLE]
- J Med Chem 2013 Dec 10.
In prostate cancer, two different types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are co-expressed and co-localize with the androgen receptor. We designed and synthesized hybrid LSD1/JmjC - "pan-KDM" - inhibitors 1-6, by coupling the skeleton of tranylcypromine 7, a known LSD1 inhibitor, with 4-carboxy-4'-carbomethoxy-2,2'-bipyridine 8 or 5-carboxy-8-hydroxyquinoline 9, two 2-oxoglutarate competitive templates developed for JmjC inhibition. Hybrid compounds 1-6 are able to simultaneously target both KDM families, and have been validated as potential antitumor agents in cells. Among them, compounds 2 and 3 increase H3K4 and H3K9 methylation levels in cells and cause growth arrest and substantial apoptosis in LNCaP prostate and HCT116 colon cancer cells. When tested in non-cancer mesenchymal progenitor (MePR) cells, 2 and 3 induced little and no apoptosis, respectively, thus showing a cancer-selective inhibiting action.
- Effects of antidepressant drugs on synaptic protein levels and dendritic outgrowth in hippocampal neuronal cultures. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Dec 1.
The alteration of hippocampal plasticity has been proposed to play a critical role in both the pathophysiology and treatment of depression. In this study, the ability of different classes of antidepressant drugs (escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine) to mediate the expression of synaptic proteins and dendritic outgrowth in rat hippocampal neurons was investigated under toxic conditions induced by B27 deprivation, which causes hippocampal cell death. Postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and synaptophysin (SYP) levels were evaluated using Western blot analyses. Additionally, dendritic outgrowth was examined to determine whether antidepressant drugs affect the dendritic morphology of hippocampal neurons in B27-deprived cultures. Escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine significantly prevented B27 deprivation-induced decreases in levels of PSD-95, BDNF, and SYP. Moreover, the independent application of fluoxetine, paroxetine, and sertraline significantly increased levels of BDNF under normal conditions. All antidepressant drugs significantly increased the total outgrowth of hippocampal dendrites under B27 deprivation. Specific inhibitors of calcium/calmodulin kinase II (CaMKII), KN-93, protein kinase A (PKA), H-89, or phosphatidylinositol 3-kinase (PI3K), LY294002, significantly decreased the effects of antidepressant drugs on dendritic outgrowth, whereas this effect was observed only with tianeptine for the PI3K inhibitor. Taken together, these results suggest that certain antidepressant drugs can enhance synaptic protein levels and encourage dendritic outgrowth in hippocampal neurons. Furthermore, effects on dendritic outgrowth likely require CaMKII, PKA, or PI3K signaling pathways. The observed effects may be may be due to chronic treatment with antidepressant drugs.
- Antidepressant treatment with MAO-inhibitors during general and regional anesthesia: a review and case report of spinal anesthesia for lower extremity surgery without discontinuation of tranylcypromine. [Journal Article, Research Support, Non-U.S. Gov't]
- Int J Clin Pharmacol Ther 2013 Oct; 51(10):763-70.
Monoamine oxidase-(MAO)-inhibitors are a treatment of last resort in treatment resistant depression, which is regarded as a condition of increased psychiatric risk. General and regional anesthesia for elective surgery during use of long-term MAO-inhibitors remains a matter of debate because of an increased risk of drug interactions and decreased sympathetic stability. A series of case reports and new comparative studies reveal the safety of anesthesia/analgesia in non-cardiac surgery without discontinuation of the MAO-inhibitor if best effort is made for maintenance of sympathetic homeostasis and if known drug interactions are avoided. Very few reports with severe adverse incidents have been noted. Severe cardiovascular morbidity, a contraindication of MAO-inhibitors, probably contributed to peri- and postoperative complications. According to new studies, the risk of pharmacokinetic drug interactions is lower for tranylcypromine than for phenelzine. In the present case, a 66-year-old psychiatric patient on permanent treatment with 20 mg/day tranylcypromine was admitted for forefoot surgery. Anesthetic premedication consisted of 7.5 mg oral midazolam. Intravenous midazolam (0.5 mg) was dispensed for intraoperative sedation. After local anesthesia of the puncture site with 30 mg isobar prilocaine, spinal anesthesia was achieved by a single shot of 13.5 mg hyperbar bupivacaine (0.5%) intrathecally. Postoperative regional and general analgesia were accomplished by a peripheral nerve block with 50 mg isobar bupivacaine as well as oral etoricoxib and oxycodone. No peri- or postoperative complications were encountered. It is concluded that general or regional anesthesia for noncardiac surgery without discontinuation of MAO-inhibitor treatment may be a safe intervention after careful evaluation of an individual's perioperative and psychiatric risk. The increased psychiatric risk in patients treated with MAO-inhibitors outweighs the increased, however manageable, perioperative risk from continuing treatment during surgery.
- Epigenetic developmental programs and adipogenesis: Implications for psychotropic induced obesity. [REVIEW]
- Epigenetics 2013 Aug 19; 8(11)
Psychotropic agents are notorious for their ability to increase fat mass in psychiatric patients. The two determinants of fat mass are the production of newly differentiated adipocytes (adipogenesis), and the volume of lipid accumulation. Epigenetic programs have a prominent role in cell fate commitments and differentiation required for adipogenesis. In parallel, epigenetic effects on energy metabolism are well supported by several genetic models. Consequently, a variety of psychotropics, often prescribed in combinations and for long periods, may utilize a common epigenetic effector path causing an increase in adipogenesis or reduction in energy metabolism. In particular, the recent discovery that G protein coupled signaling cascades can directly modify epigenetic regulatory enzymes implicates surface receptor activity by psychotropic medications. The potential therapeutic implications are also suggested by the effects of the clinically approved antidepressant tranylcypromine, also a histone demethylase inhibitor, which has impressive therapeutic effects on metabolism in the obese phenotype.
- Current place of monoamine oxidase inhibitors in the treatment of depression. [Journal Article, Research Support, Non-U.S. Gov't]
- CNS Drugs 2013 Oct; 27(10):789-97.
This paper reviews the discovery and history of the use of irreversible monoamine oxidase (MAO) inhibitors (MAOIs) such as phenelzine, tranylcypromine and isocarboxazid, as well as the second generation selective and reversible MAOIs such as the MAO-A inhibitor, moclobemide and the MAO-B inhibitor, selegiline. Data for review were identified from a literature search of OvidSP Medline and PsycInfo performed in July 2012, using the subject terms and keywords of 'monoamine oxidase inhibitors', 'major depression', 'depressive disorder' and 'depression (emotion)'. The search was limited to papers published in the English language and from 2007 onward only. Irreversible MAOIs have the potential to treat the most challenging mood disorder patients including those with treatment-resistant depression, atypical depression and bipolar depression. Unfortunately, the use of irreversible MAOIs has been declining sharply due to lack of marketing and the excessive fears of clinicians. Moreover, few clinicians now have any experience, let alone comfort, in prescribing this class of antidepressants. The newer MAOIs are available as another option for the treatment of major depression but have not replaced the irreversible MAOIs for the specific sub-types of depression for which they are now recommended in most consensus guidelines and treatment algorithms. The pharmacology, drug interactions and dietary recommendations associated with the use of MAOIs are reviewed. With the appropriate dietary restrictions and attention to potential drug interactions with serotonin and noradrenaline agents this class of drugs can be used effectively and safely. The MAOIs still represent an important element in our therapeutic armamentarium. Despite recommendations by opinion leaders and consensus guidelines for the use of MAOIs in specific sub-types of depression, the prescription rate of MAOIs is far less than expected and is decreasing. The "bad reputation" and the lack of industry support for this class of agents (especially the irreversible MAOIs) must be overcome in order to continue to provide a potentially useful treatment for a very vulnerable yet substantial sub-population of mood disorder patients.
- Rines E3 ubiquitin ligase regulates MAO-A levels and emotional responses. [Journal Article, Research Support, Non-U.S. Gov't]
- J Neurosci 2013 Aug 7; 33(32):12940-53.
Monoamine oxidase A (MAO-A), the catabolic enzyme of norepinephrine and serotonin, plays a critical role in emotional and social behavior. However, the control and impact of endogenous MAO-A levels in the brain remains unknown. Here we show that the RING finger-type E3 ubiquitin ligase Rines/RNF180 regulates brain MAO-A subset, monoamine levels, and emotional behavior. Rines interacted with MAO-A and promoted its ubiquitination and degradation. Rines knock-out mice displayed impaired stress responses, enhanced anxiety, and affiliative behavior. Norepinephrine and serotonin levels were altered in the locus ceruleus, prefrontal cortex, and amygdala in either stressed or resting conditions, and MAO-A enzymatic activity was enhanced in the locus ceruleus in Rines knock-out mice. Treatment of Rines knock-out mice with MAO inhibitors showed genotype-specific effects on some of the abnormal affective behaviors. These results indicated that the control of emotional behavior by Rines is partly due to the regulation of MAO-A levels. These findings verify that Rines is a critical regulator of the monoaminergic system and emotional behavior and identify a promising candidate drug target for treating diseases associated with emotion.
- CD86 expression as a surrogate cellular biomarker for pharmacological inhibition of the histone demethylase lysine-specific demethylase 1. [Journal Article]
- Anal Biochem 2013 Nov 1; 442(1):104-6.
There is a lack of rapid cell-based assays that read out enzymatic inhibition of the histone demethylase LSD1 (lysine-specific demethylase 1). Through transcriptome analysis of human acute myeloid leukemia THP1 cells treated with a tranylcypromine-derivative inhibitor of LSD1 active in the low nanomolar range, we identified the cell surface marker CD86 as a sensitive surrogate biomarker of LSD1 inhibition. Within 24h of enzyme inhibition, there was substantial and dose-dependent up-regulation of CD86 expression, as detected by quantitative polymerase chain reaction, flow cytometry, and enzyme-linked immunosorbent assay. Thus, the use of CD86 expression may facilitate screening of compounds with putative LSD1 inhibitory activities in cellular assays.
- Effects of the monoamine oxidase inhibitors pargyline and tranylcypromine on cellular proliferation in human prostate cancer cells. [Journal Article, Research Support, Non-U.S. Gov't]
- Oncol Rep 2013 Oct; 30(4):1587-92.
Chemotherapy is one of the therapeutic strategies that has been used for the inhibition of cancer cell proliferation in several types of cancer, including prostate cancer. Although monoamine oxidase (MAO) inhibitors, phytoestrogen and antioxidants used in chemotherapy have been systematically studied, their effects on cancer cell growth remain to be fully understood. The purpose of this study was to investigate the effects of the MAO inhibitors, pargyline and tranylcypromine on cell survival in human prostate carcinoma (LNCaP-LN3) cells. After treating LNCaP-LN3 cells with pargyline or tranylcypromine, we examined cell proliferation, cell cycle pattern, apoptosis and the expression levels of apoptosis-related genes. The proliferation of cells exposed to pargyline decreased in a dose- and time-dependent manner, while tranylcypromine-treated cells showed the opposite results. Treatment with pargyline significantly induced cell cycle arrest at the G1 phase compared to the control and tranylcypromine-treated cells. In addition, pargyline induced an increase in the cell death rate by promoting apoptosis; however, tranylcypromine had no effect on LNCaP-LN3 cells. Based on our results, we suggest that pargyline is more powerful than tranylcypromine for the treatment of human prostate cancer.
- N-acetylcysteine augmentation to tranylcypromine in treatment-resistant major depression. [Letter]
- J Clin Psychopharmacol 2013 Oct; 33(5):719-20.
- ["Addiction" to phenelzine - case report]. [Case Reports, English Abstract, Journal Article]
- Psychiatr Pol 2013 Jan-Feb; 47(1):127-34.
The use of non-selective monoamine oxidase inhibitors (IMAO) may be associated with the risk of addiction, which is confirmed by case studies published so far. Harmful use of antidepressants in patients with affective disorders and anxiety is not frequent, but due to the fact that in clinical practice can meet with this phenomenon, we present the case of a 30-year-old patient with a history of using phenelzine who presented a combination of symptoms that meet criteria for addiction. The current classification of ICD- 10 does not consist the diagnosis of dependence on antidepressants. In this case, the category F55.0: abuse of a substance which does not cause addiction, should be used. In the literature most often mentioned as a possible substances with addictive potential is a group of non-selective MAO, particularly tranylcypromine. The mechanism of non-selective MAO dependence may be associated with the similarity of their chemical structure to amphetamine (both amphetamine and IMAO are derivatives of phenylethylamine), although the mechanism of action is different. Furthermore, it was noted that there is a group of patients in whom treatment with IMAO is associated with greater risk of abuse of these substances. The study contains the characteristics of this group of patients.