Pharmaceuticals

571 KiB

Open AccessArticle

Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration

by Sama F. Sleiman, Jill Berlin, Manuela Basso, Saravanan S.Karuppagounder, Jürgen Rohr and Rajiv R. Ratan

Pharmaceuticals 2011, 4(8), 1183-1195; https://doi.org/10.3390/ph4081183 - 22 Aug 2011

Cited by 20 | Viewed by 8200

Abstract

Mithramycin A (MTM) and histone deacetylase inhibitors (HDACi) are effective therapeutic agents for cancer and neurodegenerative diseases. MTM is a FDA approved aureolic acid-type antibiotic that binds to GC-rich DNA sequences and interferes with Sp1 transcription factor binding to its target sites (GC [...] Read more.

Mithramycin A (MTM) and histone deacetylase inhibitors (HDACi) are effective therapeutic agents for cancer and neurodegenerative diseases. MTM is a FDA approved aureolic acid-type antibiotic that binds to GC-rich DNA sequences and interferes with Sp1 transcription factor binding to its target sites (GC box). HDACi, on the other hand, modulate the activity of class I and II histone deacetylases. They mediate their protective function, in part, by regulating the acetylation status of histones or transcription factors, including Sp1, and in turn chromatin accessibility to the transcriptional machinery. Because these two classes of structurally and functionally diverse compounds mediate similar therapeutic functions, we investigated whether they act on redundant or synergistic pathways to protect neurons from oxidative death. Non-protective doses of each of the drugs do not synergize to create resistance to oxidative death suggesting that these distinct agents act via a similar pathway. Accordingly, we found that protection by MTM and HDACi is associated with diminished expression of the oncogene, Myc and enhanced expression of a tumor suppressor, p21^waf1/cip1. We also find that neuroprotection by MTM or Myc knockdown is associated with downregulation of class I HDAC levels. Our results support a model in which the established antitumor drug MTM or canonical HDACi act via distinct mechanisms to converge on the downregulation of HDAC levels or activity respectively. These findings support the conclusion that an imbalance in histone acetylase and HDAC activity in favor of HDACs is key not only for oncogenic transformation, but also neurodegeneration. Full article

(This article belongs to the Special Issue HDAC Inhibitors)

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574 KiB

Open AccessArticle

Molecular Determinants of the Response of Tumor Cells to Boswellic Acids

by Tolga Eichhorn, Henry Johannes Greten and Thomas Efferth

Pharmaceuticals 2011, 4(8), 1171-1182; https://doi.org/10.3390/ph4081171 - 19 Aug 2011

Cited by 14 | Viewed by 7443

Abstract

Frankincense (Boswellia serrata, B. carterii) is used as traditional remedy to treat inflammatory diseases. The molecular effects of the active ingredients, the boswellic acids, on the immune system have previously been studied and verified in several clinical studies. Boswellic acids also [...] Read more.

Frankincense (Boswellia serrata, B. carterii) is used as traditional remedy to treat inflammatory diseases. The molecular effects of the active ingredients, the boswellic acids, on the immune system have previously been studied and verified in several clinical studies. Boswellic acids also inhibit cancer cell growth in vitro and in vivo. The molecular basis of the cytotoxicity of boswellic acids is, however, not fully understood as yet. By mRNA-based microarray, COMPARE, and hierarchical cluster analyses, we identified a panel of genes from diverse functional groups, which were significantly associated with sensitivity or resistance of a- or b-boswellic acids, such as transcription factors, signal transducers, growth regulating genes, genes involved in RNA and protein metabolism and others. This indicates that boswellic acids exert profound cytotoxicity on cancer cells by a multiplicity of molecular mechanisms. Full article

(This article belongs to the Special Issue Phytomedicine)

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485 KiB

Open AccessArticle

Synthesis and Biological Screening of 4-Benzyl-2H-phthalazine Derivatives

by Ashraf H.F. Abd El-Wahab, Hany M. Mohamed, Ahmed M. El-Agrody, Mohammed A. El-Nassag and Ahmed H. Bedair

Pharmaceuticals 2011, 4(8), 1158-1170; https://doi.org/10.3390/ph4081158 - 17 Aug 2011

Cited by 27 | Viewed by 8241

Abstract

Preparation of 4-benzyl-2-substituted phthalazin-1-one derivatives 2-8 is reported. Condensation of 4-benzyl-1-chlorophthalazine (9) with a series of different nucleophiles gave 4-benzylphthalazin-1-ylamino derivatives (10-13 and 16) and 4-amino-2-[N'-(4-benzylphthalazin-1-yl)-hydrazino]-6-arylpyrimidine-5-carbonitriles (14a,b). Interaction of 9 with ambident anions [...] Read more.

Preparation of 4-benzyl-2-substituted phthalazin-1-one derivatives 2-8 is reported. Condensation of 4-benzyl-1-chlorophthalazine (9) with a series of different nucleophiles gave 4-benzylphthalazin-1-ylamino derivatives (10-13 and 16) and 4-amino-2-[N'-(4-benzylphthalazin-1-yl)-hydrazino]-6-arylpyrimidine-5-carbonitriles (14a,b). Interaction of 9 with ambident anions was also studied. 5-Benzyl-6,6a,12-triazobenzo[a]-anthracen-7-one (15) is obtained from 9 and anthranilic acid derivatives. Treatment of 16 with (EtO)₃CH/Ac₂O under reflux afforded the corresponding ethoxymethylene derivative 17, while aqueous ammonium hydroxide treatment afforded carboxamide derivative 18. The structures of the newly synthesized derivatives were confirmed by their elemental analysis, IR,¹H NMR, ¹³C NMR and mass spectral studies. Antimicrobial activities of some selected compounds were also studied and some of these were found to exhibit promising effects against Gram-positive and Gram-negative bacteria and fungi. Full article

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1106 KiB

Open AccessReview

Aptamer-Gated Nanoparticles for Smart Drug Delivery

by Veli Cengiz Ozalp, Fusun Eyidogan and Huseyin Avni Oktem

Pharmaceuticals 2011, 4(8), 1137-1157; https://doi.org/10.3390/ph4081137 - 15 Aug 2011

Cited by 66 | Viewed by 16041

Abstract

Aptamers are functional nucleic acid sequences which can bind specific targets. An artificial combinatorial methodology can identify aptamer sequences for any target molecule, from ions to whole cells. Drug delivery systems seek to increase efficacy and reduce side-effects by concentrating the therapeutic agents [...] Read more.

Aptamers are functional nucleic acid sequences which can bind specific targets. An artificial combinatorial methodology can identify aptamer sequences for any target molecule, from ions to whole cells. Drug delivery systems seek to increase efficacy and reduce side-effects by concentrating the therapeutic agents at specific disease sites in the body. This is generally achieved by specific targeting of inactivated drug molecules. Aptamers which can bind to various cancer cell types selectively and with high affinity have been exploited in a variety of drug delivery systems for therapeutic purposes. Recent progress in selection of cell-specific aptamers has provided new opportunities in targeted drug delivery. Especially functionalization of nanoparticles with such aptamers has drawn major attention in the biosensor and biomedical areas. Moreover, nucleic acids are recognized as an attractive building materials in nanomachines because of their unique molecular recognition properties and structural features. A active controlled delivery of drugs once targeted to a disease site is a major research challenge. Stimuli-responsive gating is one way of achieving controlled release of nanoparticle cargoes. Recent reports incorporate the structural properties of aptamers in controlled release systems of drug delivering nanoparticles. In this review, the strategies for using functional nucleic acids in creating smart drug delivery devices will be explained. The main focus will be on aptamer-incorporated nanoparticle systems for drug delivery purposes in order to assess the future potential of aptamers in the therapeutic area. Special emphasis will be given to the very recent progress in controlled drug release based on molecular gating achieved with aptamers. Full article

(This article belongs to the Special Issue Aptamer-Based Therapeutics)

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411 KiB

Open AccessReview

The Endocannabinoid System as Pharmacological Target Derived from Its CNS Role in Energy Homeostasis and Reward. Applications in Eating Disorders and Addiction

by Maria-Paz Viveros, Francisco-Javier Bermúdez-Silva, Ana-Belén Lopez-Rodriguez and Edward J. Wagner

Pharmaceuticals 2011, 4(8), 1101-1136; https://doi.org/10.3390/ph4081101 - 10 Aug 2011

Cited by 11 | Viewed by 11604

Abstract

The endocannabinoid system (ECS) has been implicated in many physiological functions, including the regulation of appetite, food intake and energy balance, a crucial involvement in brain reward systems and a role in psychophysiological homeostasis (anxiety and stress responses). We first introduce this important [...] Read more.

The endocannabinoid system (ECS) has been implicated in many physiological functions, including the regulation of appetite, food intake and energy balance, a crucial involvement in brain reward systems and a role in psychophysiological homeostasis (anxiety and stress responses). We first introduce this important regulatory system and chronicle what is known concerning the signal transduction pathways activated upon the binding of endogenous cannabinoid ligands to the G_i/0-coupled CB1 cannabinoid receptor, as well as its interactions with other hormones and neuromodulators which can modify endocannabinoid signaling in the brain. Anorexia nervosa (AN) and bulimia nervosa (BN) are severe and disabling psychiatric disorders, characterized by profound eating and weight alterations and body image disturbances. Since endocannabinoids modulate eating behavior, it is plausible that endocannabinoid genes may contribute to the biological vulnerability to these diseases. We present and discuss data suggesting an impaired endocannabinoid signaling in these eating disorders, including association of endocannabinoid components gene polymorphisms and altered CB1-receptor expression in AN and BN. Then we discuss recent findings that may provide new avenues for the identification of therapeutic strategies based on the endocannabinod system. In relation with its implications as a reward-related system, the endocannabinoid system is not only a target for cannabis but it also shows interactions with other drugs of abuse. On the other hand, there may be also a possibility to point to the ECS as a potential target for treatment of drug-abuse and addiction. Within this framework we will focus on enzymatic machinery involved in endocannabinoid inactivation (notably fatty acid amide hydrolase or FAAH) as a particularly interesting potential target. Since a deregulated endocannabinoid system may be also related to depression, anxiety and pain symptomatology accompanying drug-withdrawal states, this is an area of relevance to also explore adjuvant treatments for improving these adverse emotional reactions. Full article

(This article belongs to the Special Issue Drug Abuse Targets)

1912 KiB

Open AccessReview

Beta-Blockers and Oxidative Stress in Patients with Heart Failure

by Kazufumi Nakamura, Masato Murakami, Daiji Miura, Kei Yunoki, Kenki Enko, Masamichi Tanaka, Yukihiro Saito, Nobuhiro Nishii, Toru Miyoshi, Masashi Yoshida, Hiroki Oe, Norihisa Toh, Satoshi Nagase, Kunihisa Kohno, Hiroshi Morita, Hiromi Matsubara, Kengo F Kusano, Tohru Ohe and Hiroshi Ito

Pharmaceuticals 2011, 4(8), 1088-1100; https://doi.org/10.3390/ph4081088 - 5 Aug 2011

Cited by 53 | Viewed by 12987

Abstract

Oxidative stress has been implicated in the pathogenesis of heart failure. Reactive oxygen species (ROS) are produced in the failing myocardium, and ROS cause hypertrophy, apoptosis/cell death and intracellular Ca²⁺ overload in cardiac myocytes. ROS also cause damage to lipid cell membranes [...] Read more.

Oxidative stress has been implicated in the pathogenesis of heart failure. Reactive oxygen species (ROS) are produced in the failing myocardium, and ROS cause hypertrophy, apoptosis/cell death and intracellular Ca²⁺ overload in cardiac myocytes. ROS also cause damage to lipid cell membranes in the process of lipid peroxidation. In this process, several aldehydes, including 4-hydroxy-2-nonenal (HNE), are generated and the amount of HNE is increased in the human failing myocardium. HNE exacerbates the formation of ROS, especially H₂O₂ and ·OH, in cardiomyocytes and subsequently ROS cause intracellular Ca²⁺ overload. Treatment with beta-blockers such as metoprolol, carvedilol and bisoprolol reduces the levels of oxidative stress, together with amelioration of heart failure. This reduction could be caused by several possible mechanisms. First, the beta-blocking effect is important, because catecholamines such as isoproterenol and norepinephrine induce oxidative stress in the myocardium. Second, anti-ischemic effects and negative chronotropic effects are also important. Furthermore, direct antioxidative effects of carvedilol contribute to the reduction of oxidative stress. Carvedilol inhibited HNE-induced intracellular Ca²⁺ overload. Beta-blocker therapy is a useful antioxidative therapy in patients with heart failure. Full article

(This article belongs to the Special Issue Betablockers)

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550 KiB

Open AccessReview

The Phosphatidylinositol 3-Kinase/mTor Pathway as a Therapeutic Target for Brain Aging and Neurodegeneration

by David Heras-Sandoval, Evangelina Avila-Muñoz and Clorinda Arias

Pharmaceuticals 2011, 4(8), 1070-1087; https://doi.org/10.3390/ph4081070 - 4 Aug 2011

Cited by 21 | Viewed by 9762

Abstract

Many pathological conditions are associated with phosphatidylinositol 3-kinase (PI3K) dysfunction, providing an incentive for the study of the effects of PI3K modulation in different aspects of diabetes, cancer, and aging. The PI3K/AKT/mTOR pathway is a key transducer of brain metabolic and mitogenic signals [...] Read more.

Many pathological conditions are associated with phosphatidylinositol 3-kinase (PI3K) dysfunction, providing an incentive for the study of the effects of PI3K modulation in different aspects of diabetes, cancer, and aging. The PI3K/AKT/mTOR pathway is a key transducer of brain metabolic and mitogenic signals involved in neuronal proliferation, differentiation, and survival. In several models of neurodegenerative diseases associated with aging, the PI3K/AKT pathway has been found to be dysregulated, suggesting that two or more initiating events may trigger disease formation in an age-related manner. The search for chemical compounds able to modulate the activity of the PI3K/AKT/mTOR pathway is emerging as a potential therapeutic strategy for the treatment and/or prevention of some metabolic defects associated with brain aging. In the current review, we summarize some of the critical actions of PI3K in brain function as well as the evidence of its involvement in aging and Alzheimer’s disease. Full article

(This article belongs to the Special Issue PI3 Kinase Inhibitors)

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Pharmaceuticals, Volume 4, Issue 8 (August 2011) – 7 articles , Pages 1070-1195

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