Pharmaceuticals

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Open AccessCorrection

Qandil, A.M., Synthesis and Spectroscopic Analysis of Novel 1H-Benzo[d]imidazolylphenylsulfonylpiperazines. Pharmaceuticals 2012, 5, 460-468

by Amjad M. Qandil

Pharmaceuticals 2012, 5(9), 1044; https://doi.org/10.3390/ph5091044 - 24 Sep 2012

Viewed by 4251

Abstract

We have found the following errors in the title of this article which was recently published in Pharmaceuticals [1]. [...] Full article

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Open AccessArticle

Evaluation of the Combined Effects of Stilbenoid from Shorea gibbosa and Vancomycin against Methicillin-Resistant Staphylococcus aureus (MRSA)

by Dayang Fredalina Basri, Chan Kin Luoi, Abdul Muin Azmi and Jalifah Latip

Pharmaceuticals 2012, 5(9), 1032-1043; https://doi.org/10.3390/ph5091032 - 20 Sep 2012

Cited by 24 | Viewed by 7448

Abstract

The aim of this study is to determine the combined effects of stilbenoids from Shorea gibbosa and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). A total of nine pure compounds, five stilbenoid dimers ε-viniferin, ampelopsin A, balanocarpol, laevifonol and diptoindonesin G and four stilbenoid [...] Read more.

The aim of this study is to determine the combined effects of stilbenoids from Shorea gibbosa and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). A total of nine pure compounds, five stilbenoid dimers ε-viniferin, ampelopsin A, balanocarpol, laevifonol and diptoindonesin G and four stilbenoid trimers a-viniferin, johorenol A, ampelopsin E and vaticanol G were evaluated for their antibacterial activities against ATCC 33591 and a HUKM clinical isolate. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for each active compound were determined using the serial microdilution and plate-streak techniques. The combined effect of stilbenoids with vancomycin against MRSA was evaluated using the checkerboard assay to determine their fractional inhibitory concentration (FIC) index values. The MIC value of a-viniferin on both MRSA strains was 100 μg/mL, whereas those of johorenol A on ATCC 33591 and HUKM strain were 100 μg/mL and 200 μg/mL, respectively. The MIC values of ampelopsin E and vaticanol G were higher than 400 μg/mL. Out of the five stilbenoid dimers, only ε-viniferin was capable of inhibiting the growth of both MRSA strains at MIC 400 μg/mL. The MBC value of ε-viniferin, a-viniferin and johorenol A showed bacteriostatic action against MRSA. The FIC index value of ε-viniferin and a-viniferin in combination with vancomycin showed an additive effect (0.5 < FIC ≤ 2.0) against both MRSA strains. Johorenol A-vancomycin combination was also additive against HUKM strain, but it showed synergistic interaction with vancomycin against ATCC 33591 (FIC < 0.5). Stilbenoid compounds from Shorea gibbosa have anti-MRSA activity and huge potential as an alternative phytotherapy in combating MRSA infections. Full article

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Open AccessReview

Why and How the Old Neuroleptic Thioridazine Cures the XDR-TB Patient

by Leonard Amaral and Joseph Molnar

Pharmaceuticals 2012, 5(9), 1021-1031; https://doi.org/10.3390/ph5091021 - 17 Sep 2012

Cited by 10 | Viewed by 6654

Abstract

This mini-review provides the entire experimental history of the development of the old neuroleptic thioridazine (TZ) for therapy of antibiotic resistant pulmonary tuberculosis infections. TZ is effective when used in combination with antibiotics to which the initial Mycobacterium tuberculosis was resistant. Under proper [...] Read more.

This mini-review provides the entire experimental history of the development of the old neuroleptic thioridazine (TZ) for therapy of antibiotic resistant pulmonary tuberculosis infections. TZ is effective when used in combination with antibiotics to which the initial Mycobacterium tuberculosis was resistant. Under proper cardiac evaluation procedures, the use of TZ is safe and does not produce known cardiopathy such as prolongation of QT interval. Because TZ is cheap, it should be considered for therapy of XDR and TDR-Mtb patients in economically disadvantaged countries. Full article

(This article belongs to the Special Issue Antituberculosis Drugs)

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Open AccessReview

Heat Shock Protein 90 (Hsp90) Expression and Breast Cancer

by Flora Zagouri, Evangelos Bournakis, Konstantinos Koutsoukos and Christos A. Papadimitriou

Pharmaceuticals 2012, 5(9), 1008-1020; https://doi.org/10.3390/ph5091008 - 12 Sep 2012

Cited by 46 | Viewed by 7436

Abstract

Hsp90 is an abundant protein in mammalian cells. It forms several discrete complexes, each containing distinct groups of co-chaperones that assist protein folding and refolding during stress, protein transport and degradation. It interacts with a variety of proteins that play key roles in [...] Read more.

Hsp90 is an abundant protein in mammalian cells. It forms several discrete complexes, each containing distinct groups of co-chaperones that assist protein folding and refolding during stress, protein transport and degradation. It interacts with a variety of proteins that play key roles in breast neoplasia including estrogen receptors, tumor suppressor p53 protein, angiogenesis transcription factor HIF-1alpha, antiapoptotic kinase Akt, Raf-1 MAP kinase and a variety of receptor tyrosine kinases of the erbB family. Elevated Hsp90 expression has been documented in breast ductal carcinomas contributing to the proliferative activity of breast cancer cells; whilst a significantly decreased Hsp90 expression has been shown in infiltrative lobular carcinomas and lobular neoplasia. Hsp90 overexpression has been proposed as a component of a mechanism through which breast cancer cells become resistant to various stress stimuli. Therefore, pharmacological inhibition of HSPs can provide therapeutic opportunities in the field of cancer treatment. 17-allylamino,17-demethoxygeldanamycin is the first Hsp90 inhibitor that has clinically been investigated in phase II trial, yielding promising results in patients with HER2-overexpressing metastatic breast cancer, whilst other Hsp90 inhibitors (retaspimycin HCL, NVP-AUY922, NVP-BEP800, CNF2024/BIIB021, SNX-5422, STA-9090, etc.) are currently under evaluation. Full article

(This article belongs to the Special Issue Hsp90 Inhibitors)

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Open AccessReview

Applications of Cell-Penetrating Peptides for Tumor Targeting and Future Cancer Therapies

by Jakob Regberg, Artita Srimanee and Ülo Langel

Pharmaceuticals 2012, 5(9), 991-1007; https://doi.org/10.3390/ph5090991 - 12 Sep 2012

Cited by 120 | Viewed by 10771

Abstract

Cell-penetrating peptides provide a highly promising strategy for intracellular drug delivery. One relevant clinical application of cell-penetrating peptides is cancer therapeutics. Peptide based delivery could increase the uptake of drugs in tumor cells and thereby increase the efficacy of the treatment, either of [...] Read more.

Cell-penetrating peptides provide a highly promising strategy for intracellular drug delivery. One relevant clinical application of cell-penetrating peptides is cancer therapeutics. Peptide based delivery could increase the uptake of drugs in tumor cells and thereby increase the efficacy of the treatment, either of conventional small molecular drugs or oligonucleotide based therapeutics. This review is focused on the cancer applications of cell penetrating peptides as delivery systems; different aspects of drug loading, cargoes and delivery are discussed together with methods for targeted delivery, activatable cell-penetrating peptides and transducible agents coupled to cell-penetrating peptides. Full article

(This article belongs to the Special Issue Cell-penetrating Peptides 2012)

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Open AccessReview

Epigenetic Control and Cancer: The Potential of Histone Demethylases as Therapeutic Targets

by Fernando Lizcano and Jeison Garcia

Pharmaceuticals 2012, 5(9), 963-990; https://doi.org/10.3390/ph5090963 - 12 Sep 2012

Cited by 16 | Viewed by 8500

Abstract

The development of cancer involves an immense number of factors at the molecular level. These factors are associated principally with alterations in the epigenetic mechanisms that regulate gene expression profiles. Studying the effects of chromatin structure alterations, which are caused by the addition/removal [...] Read more.

The development of cancer involves an immense number of factors at the molecular level. These factors are associated principally with alterations in the epigenetic mechanisms that regulate gene expression profiles. Studying the effects of chromatin structure alterations, which are caused by the addition/removal of functional groups to specific histone residues, are of great interest as a promising way to identify markers for cancer diagnosis, classify the disease and determine its prognosis, and these markers could be potential targets for the treatment of this disease in its different forms. This manuscript presents the current point of view regarding members of the recently described family of proteins that exhibit histone demethylase activity; histone demethylases are genetic regulators that play a fundamental role in both the activation and repression of genes and whose expression has been observed to increase in many types of cancer. Some fundamental aspects of their association with the development of cancer and their relevance as potential targets for the development of new therapeutic strategies at the epigenetic level are discussed in the following manuscript. Full article

(This article belongs to the Special Issue Epigenetic Therapies and Biomarkers)

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Open AccessReview

Molecular Dynamics Simulations of Hsp90 with an Eye to Inhibitor Design

by Elisabetta Moroni, Giulia Morra and Giorgio Colombo

Pharmaceuticals 2012, 5(9), 944-962; https://doi.org/10.3390/ph5090944 - 10 Sep 2012

Cited by 1 | Viewed by 7021

Abstract

Proteins carry out their functions through interactions with different partners. Dynamic conformational switching among different structural sub-states favors the adaptation to the shapes of the different partners. Such conformational changes can be determined by diverse biochemical factors, such as ligand-binding. Atomic level investigations [...] Read more.

Proteins carry out their functions through interactions with different partners. Dynamic conformational switching among different structural sub-states favors the adaptation to the shapes of the different partners. Such conformational changes can be determined by diverse biochemical factors, such as ligand-binding. Atomic level investigations of the mechanisms that underlie functional dynamics may provide new opportunities for the discovery of leads that target disease-related proteins. In this review, we report our views and approaches on the development of novel and accurate physical-chemistry-based models for the characterization of the salient aspects of the ligand-regulated dynamics of Hsp90, and on the exploitation of such new knowledge for the rational discovery of inhibitors of the chaperone. Full article

(This article belongs to the Special Issue Hsp90 Inhibitors)

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Open AccessArticle

Differential Cellular and Molecular Effects of Butyrate and Trichostatin A on Vascular Smooth Muscle Cells

by Shirlette G. Milton, Omana P. Mathew, Frank M. Yatsu and Kasturi Ranganna

Pharmaceuticals 2012, 5(9), 925-943; https://doi.org/10.3390/ph5090925 - 04 Sep 2012

Cited by 12 | Viewed by 8160

Abstract

The histone deacetylase (HDAC) inhibitors, butyrate and trichostatin A (TSA), are epigenetic histone modifiers and proliferation inhibitors by downregulating cyclin D1, a positive cell cycle regulator, and upregulating p21Cip1 and INK family of proteins, negative cell cycle regulators. Our recent study indicated cyclin [...] Read more.

The histone deacetylase (HDAC) inhibitors, butyrate and trichostatin A (TSA), are epigenetic histone modifiers and proliferation inhibitors by downregulating cyclin D1, a positive cell cycle regulator, and upregulating p21Cip1 and INK family of proteins, negative cell cycle regulators. Our recent study indicated cyclin D1 upregulation in vascular smooth muscle cells (VSMC) that are proliferation-arrested by butyrate. Here we investigate whether cyclin D1 upregulation is a unique response of VSMC to butyrate or a general response to HDAC inhibitors (HDACi) by evaluating the effects of butyrate and TSA on VSMC. While butyrate and TSA inhibit VSMC proliferation via cytostatic and cytotoxic effects, respectively, they downregulate cdk4, cdk6, and cdk2, and upregulate cyclin D3, p21Cip1 and p15INK4B, and cause similar effects on key histone H3 posttranslational modifications. Conversely, cyclin D1 is upregulated by butyrate and inhibited by TSA. Assessment of glycogen synthase 3-dependent phosphorylation, subcellular localization and transcription of cyclin D1 indicates that differential effects of butyrate and TSA on cyclin D1 levels are linked to disparity in cyclin D1 gene expression. Disparity in butyrate- and TSA-induced cyclin D1 may influence transcriptional regulation of genes that are associated with changes in cellular morphology/cellular effects that these HDACi confer on VSMC, as a transcriptional modulator. Full article

(This article belongs to the Special Issue Epigenetic Therapies and Biomarkers)

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Open AccessReview

The Tissue Selective Estrogen Complex: A Promising New Menopausal Therapy

by Barry S. Komm and Sebastian Mirkin

Pharmaceuticals 2012, 5(9), 899-924; https://doi.org/10.3390/ph5090899 - 04 Sep 2012

Cited by 7 | Viewed by 6694

Abstract

Menopause is associated with health concerns including vasomotor symptoms, vulvar/vaginal atrophy (VVA), and osteoporosis. Estrogen therapy or combined estrogen-progestin therapy (EPT) are primary treatment options for menopausal symptom relief and osteoporosis prevention. Because EPT has been associated with some safety/tolerability concerns relating to [...] Read more.

Menopause is associated with health concerns including vasomotor symptoms, vulvar/vaginal atrophy (VVA), and osteoporosis. Estrogen therapy or combined estrogen-progestin therapy (EPT) are primary treatment options for menopausal symptom relief and osteoporosis prevention. Because EPT has been associated with some safety/tolerability concerns relating to undesirable effects of estrogen and progestin, alternative options are needed. The tissue selective estrogen complex (TSEC) is a novel class of agents pairing a selective estrogen receptor modulator (SERM) with 1 or more estrogens. The TSEC combines the established efficacy of estrogens on menopausal symptoms and bone with the protective effects of a SERM on the reproductive tract. The pairing of bazedoxifene (BZA) with conjugated estrogens (CE) has been evaluated in a series of phase 3 clinical trials. BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg have shown efficacy in reducing the frequency and severity of hot flushes, relieving VVA symptoms, and maintaining bone mass while protecting the endometrium and breast. These BZA/CE doses have been associated with a favorable safety/tolerability profile, with higher rates of cumulative amenorrhea and lower incidences of breast pain than those reported for EPT. Thus, BZA/CE may be a promising alternative to conventional EPT for treating non-hysterectomized, postmenopausal women. Full article

(This article belongs to the Special Issue Hormone Therapy)

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Open AccessReview

Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms

by Xiangyi Lu, Luan Wang and Douglas M. Ruden

Pharmaceuticals 2012, 5(9), 890-898; https://doi.org/10.3390/ph5090890 - 30 Aug 2012

Cited by 9 | Viewed by 6720

Abstract

In this review, we focus on how inhibitors of Hsp90 can help prevent the resistance to anti-cancer drugs by synergistically increasing their cancer killing abilities and thereby allowing them to function at much lower concentrations than normally used. Hsp90 helps to fold numerous [...] Read more.

In this review, we focus on how inhibitors of Hsp90 can help prevent the resistance to anti-cancer drugs by synergistically increasing their cancer killing abilities and thereby allowing them to function at much lower concentrations than normally used. Hsp90 helps to fold numerous client proteins, such as Akt, Raf, Src, chromatin-modifying proteins, nuclear hormone receptors, and kinetochore assembly proteins. We discuss four mechanisms by which Hsp90 inhibitors can potentially synergize with anti-cancer drugs: by making a drug-resistant protein that is a client for Hsp90 more sensitive to the drug, by increasing chromosomal aneuploidy and the effectiveness of DNA-damaging drugs, by inhibiting Trithorax proteins which trimethylate histone 3 at lysine 4 (H3K4me3) and thereby decreasing expression of tumor promoter genes, and by interacting with the negative elongation factor (NELF) complex in tumors. We also explain how the evolutionary capacitor function of Hsp90 can be exploited with inhibitors of Hsp90 by exposing new protein variants that can be targeted with other drugs, thereby opening new avenues of combination drug therapy to treat cancer. We believe that inhibition of these processes can increase the efficacy of Hsp90 inhibitors with other anti-cancer drugs. Full article

(This article belongs to the Special Issue Hsp90 Inhibitors)

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Pharmaceuticals, Volume 5, Issue 9 (September 2012) – 10 articles , Pages 890-1044

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