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Anti-Cancer Agents in Medicinal Chemistry (v.12, #6)

Neutrophil Elastase as a Target in Lung Cancer by Gautier Moroy (pp. 565-579).
Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, cleaving for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i.e. morphoelastokines which potently stimulate cancer cell invasiveness and angiogenesis. Since decades, researchers identified natural compounds and/or synthesized agents which antagonize HNE activity that will be described in this review article. Some of these compounds might be of value as therapeutic agents in lung cancer. However, it is now widely accepted that lung tumor invasion and metastasis involve proteolytic cascades. Accordingly, we will here mainly focus our attention to natural substances able to display a dual inhibitory capacity (i.e. lipids and derivatives, phenolics) towards HNE and matrix metalloproteinases (MMPs), particularly MMP-2. To that purpose, we recently synthesize substances named “LipoGalardin” (Moroy G. et al., Biochem. Pharmacol., 2011, 81(5), 626-635) exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor.

Anticoagulant and Fibrinolytic Drugs – Possible Agents in Treatment of Lung Cancer? by Vladimir Bobek (pp. 580-588).
The effect of anticoagulant adjuvant anti-tumor therapy depends on the cancer type and stage and on the type of the used anticoagulant drug. A striking response rate was described in experiments involving human patients with lung cancer. The aim of this study is to review anticoagulant and fibrinolytic drugs as antitumor agents with focus on their clinical use. The first part of the review evaluates the results of clinical studies. The results of early clinical research are promising and observations suggest novel approaches to the experimental therapy of lung cancer. The second part of the review shortly describes the problem of thrombosis in patients with lung cancer (incidence of thromboembolic disease and its pathogenesis). The third part briefly describes the antimetastatic and antitumor attributes of anticoagulants and fibrinolytics.

Current and Emerging Strategies in Bladder Cancer by Simone Carradori (pp. 589-603).
Urothelial cell carcinoma is one of the most common malignancies of the urinary tract. The standard of care, intravesical chemo- and immunotherapy, while effective, is associated with a considerable side-effect profile and approximately 30% of patients either fail to respond to treatment or suffer recurrent disease within 5 years. In the setting of muscle-invasive urothelial carcinoma, use of neoadjuvant chemotherapy is associated with overall survival benefit. Muscle invasive bladder cancer is life threatening, showing modest chemosensitivity, and usually requires radical cystectomy. Although bladder cancer is fairly well-genetically characterized, clinical trials with molecularly targeted agents have, in comparison to other solid tumors, been few in number and largely unsuccessful. Hence, bladder cancer represents a considerable opportunity and challenge for alternative therapies. In this review, we will focus on promising global or pathway-based approaches (epigenetic modulators, kinase inhibitors, angiogenesis blockage, peroxisome proliferator-activated receptor γ agonists, apoptosis inductors, virus therapy) supported by a deeper understanding of molecular biology of urothelial carcinoma, which have been recently tested in clinical trials.

Gallium Phthalocyanine Photosensitizers: Carboxylation Enhances the Cellular Uptake and Improves the Photodynamic Therapy of Cancers by Jin F. Zhao (pp. 604-610).
The octacarboxyl gallium (GaPcC) and metal-free (H2PcC) phthalocyanines were prepared using the carboxyl as the peripheral substituent. The carboxylation improves the intracellular delivery of these two PcCs into KB and QGY cancer cells as compared to that of sulfonated aluminum phthalocyanines (AlPcS), a popularly used photosensitizer (PS). Moreover, GaPcC maintains high photoproduction of singlet oxygen. With a short incubation time of 3 hours, GaPcC accumulates sufficiently in both KB and QGY cells and improves photodynamic therapy (PDT) by effectively killing these cancer cells. AlPcS and H2PcC show much lower PDT effects under the same conditions, because AlPcS have a slow cellular uptake rate resulting in a low cellular amount and the ability of H2PcC to produce 1O2 is low. Carboxylation is a promising way to prepare water-soluble metal phthalocyanines (MPcCs) and facilitates the cellular uptake of MPcCs for PDT improvement.

Anticancer Activity and Anti-inflammatory Studies of 5-Aryl-1,4-benzodiazepine Derivatives by Cortez-Maya Sandra (pp. 611-618).
A series of 5-aryl-1,4-benzodiazepines with chloro- or fluoro-substituents in the second ring have been synthesized and their anti-inflammatory, myeloperoxidase and anticancer properties studied. The synthesized compounds showed potential anti-inflammatory and anticancer activities, which were enhanced in the presence of a chloro-substituent in the second ring of the 5-aryl-1,4- benzodiazepine.

Cranberry as Promising Natural Source of Potential Anticancer Agents: Current Evidence and Future Perspectives by Athanasios Katsargyris (pp. 619-630).
Background: Accumulating evidence suggest that dietary modification can lower the risk for several cancer types’ development. Cranberry in particular, has been shown to have anti-oxidative, -inflammatory and -proliferative properties in vitro. Objective: To present the latest knowledge regarding the role of cranberry extracts against human cancer several types. Methods: A review of the literature documenting both in vitro and in vivo anti-cancer effects of whole cranberry and/or its extracts is conducted. Conclusions: Current data provide evidence for several anti-cancer properties of either whole cranberry and/or its extracts. The discovery of the specific cranberry components and the appropriate concentrations that exert such beneficial effects along with verification of the preliminary in vitro results in in vivo settings could potentially lead to the invention of novel safer and efficient anti-cancer therapeutic agents.

The Role of Cdc25A in the Regulation of Cell Proliferation and Apoptosis by Tao Shen (pp. 631-639).
Cell division cycle 25 A (Cdc25A), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (CDKs), such as CDK2, CDK4, and CDK6, and positively regulates the activities of CDKs that lead to cell cycle progression. In addition, Cdc25A also acts as a regulator of apoptosis. Overexpression of Cdc25A promotes tumorigenesis, and is frequently observed in various types of cancer. Here we briefly summarize current understanding of the role of Cdc25A in cell proliferation and apoptosis, as well as the impact of overexpression of Cdc25A on tumorigenesis.

Effects of Bioactive Compounds from Carrots (Daucus carota L.), Polyacetylenes, Beta-Carotene and Lutein on Human Lymphoid Leukaemia Cells by Rana G. Zaini (pp. 640-652).
New therapies for leukaemia are urgently needed. Carrots have been suggested as a potential treatment for leukaemia in traditional medicine and have previously been studied in other contexts as potential sources of anticancer agents. Indicating that carrots may contain bioactive compounds, which may show potential in leukaemia therapies. This study investigated the effects of five fractions from carrot juice extract (CJE) on human lymphoid leukaemia cell lines, together with five purified bioactive compounds found in Daucus carota L, including: three polyacetylenes (falcarinol, falcarindiol and falcarindiol-3-acetate) and two carotenoids (beta-carotene and lutein). Their effects on induction of apoptosis using Annexin V/PI and Caspase 3 activity assays analysed via flow cytometry and inhibition of cellular proliferation using Cell Titer Glo assay and cell cycle analysis were investigated. Treatment of all three lymphoid leukaemia cell lines with the fraction from carrot extracts which contained polyacetylenes and carotenoids was significantly more cytotoxic than the 4 other fractions. Treatments with purified polyacetylenes also induced apoptosis in a dose and time responsive manner. Moreover, falcarinol and falcarindiol-3-acetate isolated from Daucus carota L were more cytotoxic than falcarindiol. In contrast, the carotenoids showed no significant effect on either apoptosis or cell proliferation in any of the cells investigated. This suggests that polyacetylenes rather than beta-carotene or lutein are the bioactive components found in Daucus carota L and could be useful in the development of new leukemic therapies. Here, for the first time, the cytotoxic effects of polyacetylenes have been shown to be exerted via induction of apoptosis and arrest of cell cycle.

A New 4-phenyl-1,8-naphthyridine Derivative Affects Carcinoma Cell Proliferation by Impairing Cell Cycle Progression and Inducing Apoptosis by Antonella Capozzi (pp. 653-662).
In targeted cancer therapy the search for novel molecules led to the discovery of a plethora of small organic molecules inhibiting cancer cell proliferation. Among these, quinazoline and derivatives, such as quinolines and naphthyridines, have been considered as of particular interest. One of these, the naphthyridine derivative 4-phenyl-2,7-di(piperazin-1-yl)-1,8-naphthyridine, has been analyzed in detail in the present work. We found that this compound elicited a powerful anti-proliferative activity on carcinoma cells, with IC50 values comparable with paradigmatic microtubule-deranging drugs. The mechanisms underlying this effect were seemingly due to a framework of cellular alterations that include peculiar alterations of mitochondria, i.e. an increase of mitochondrial membrane potential (MMP), followed by the typical MMP loss leading to the release of apoptogenic factors, and cell death by apoptosis. Furthermore, the analysis of cell cycle revealed that a significant percentage of treated cells was in G2/M phase. This block was seemingly due to a target effect of the naphthyridine derivative on microtubular network dynamic instability, which impaired mitotic spindle formation, possibly leading to mitotic catastrophy. Since the dual effects of naphthyridine derivative on cell cycle and mitotic spindle were obtained at very low concentrations, i.e. micromolar concentrations, we hypothesize that this compound could represent a new promising tool in the control of cancer cell proliferation.

Anticancer Effects of the Organosilicon Multidrug Resistance Modulator SILA 421 by Ulrike Olszewski (pp. 663-671).
1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis{3-[1(4-butylpiperazinyl)]-propyl}-disiloxan-tetrahydrochlorid (SILA 421) is a compound that was developed as modulator of the ABC cassette transporter P-glycoprotein. Furthermore, it exerted antimicrobial toxicity, vascular effects, downregulation of chaperone induction and plasmid curing in bacterial cells. Here, this drug was found to possess cytotoxic activity against a panel of human cancer cell lines that do not overexpress P-gp, with 50% inhibitory concentrations ranging between 1.75±0.38 μM for GLC14 small cell lung cancer and 34.00±4.75 μM for PC-3 prostate cancer cells. HL-60 leukemia and MDA-MB-435 breast cancer cells exhibited cell cycle arrest and apoptotic cell death in response to SILA 421. Assessment of global gene expression of SILA 421-treated HL-60 cells was employed to identify cellular pathways affected by the compound and revealed disturbance of DNA replication, transcription and production of apparently misfolded proteins. Endoplasmatic reticulum stress and downregulation of cell cycle, cellular repair mechanisms and growth factor-related signaling cascades eventually resulted in induction of apoptosis in this cell line. In addition to the well established P-gp inhibitory effect of SILA compounds, reversal of resistance to taxanes, which had been reported for SILA 421 and the related molecule SILA 409, may be linked to downregulation of gene expression of kinesins. Interference with DNA replication and transcription seems to be the common denominator of antimicrobial activity and plasmid curing, as well as anticancer toxicity in human cell lines. Thus, in consideration of the full range of putative cellular targets found in the present work, the application of these SILA compounds for treatment of tumors should be further evaluated.

Triple-negative Breast Cancer and Poly(ADP-ribose) Polymerase Inhibitors by Youngjin Park (pp. 672-677).
Recent gene profiling studies have identified at least 5 major subtypes of breast cancer, including normal type, luminal A type, luminal B type, human epidermal growth factor receptor (HER)-2 positive type, and basal-like type. Triple-negative breast cancer (TNBC), showing no or low expressions of estrogen receptor (ER), progesterone receptor (PgR), and HER2, considered important clinical biomarkers, accounts for 10% to 20% of all breast cancers. Hormonal therapy and molecular targeted therapy are not indicated for the management of TNBC, resulting in poor outcomes. Because TNBC lacks clear-cut therapeutic targets, effective treatment strategies remain to be established. However, TNBC is known to share similar biologic characteristics with basal-like type breast cancer and is often accompanied by loss of functional BRCA, a gene-modifying enzyme. Breast cancer with BRCA1 or BRCA2 mutations is accompanied by activation of the enzyme poly(ADP-ribose) polymerase (PARP). PARP, a DNA base-excision repair enzyme, is known to play a central role in gene repair, along with BRCA. Because some breast cancers with BRCA1 or BRCA2 mutations are TNBC, the suppression of PARP has attracted attention as a new treatment strategy for TNBC. In this article, we review the clinical characteristics of TNBC, discuss problems in treatment, and briefly summarize the international development status of PARP inhibitors.

Chemoinformatics in Multi-target Drug Discovery for Anti-cancer Therapy: In Silico Design of Potent and Versatile Anti-brain Tumor Agents by Alejandro Speck-Planche (pp. 678-685).
A brain tumor (BT) constitutes a neoplasm located in the brain or the central spinal canal. The number of new diagnosed cases with BT increases with the pass of the time. Understanding the biology of BT is essential for the development of novel therapeutic strategies, in order to prevent or deal with this disease. An active area for the search of new anti-BT therapies is the use of Chemoinformatics and/or Bioinformatics toward the design of new and potent anti-BT agents. The principal limitation of all these approaches is that they consider small series of structurally related compounds and/or the studies are realized for only one target like protein. The present work is an effort to overcome this problem. We introduce here the first Chemoinformatics multi-target approach for the in silico design and prediction of anti-BT agents against several cell lines. Here, a fragment-based QSAR model was developed. The model correctly classified 89.63% and 90.93% of active and inactive compounds respectively, in training series. The validation of the model was carried out by using prediction series which showed 88.00% of correct classification for active and 88.59% for inactive compounds. Some fragments were extracted from the molecules and their contributions to anti-BT activity were calculated. Several fragments were identified as potential substructural features responsible of anti-BT activity and new molecular entities designed from fragments with positive contributions were suggested as possible anti-BT agents.
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