Current Medicinal Chemistry - Volume 19, Issue 5, 2012

Despite worldwide research and major development efforts in oncology therapeutics, approximately 50% of cancer patients remain associated with dismal prognoses. More than 85% of the current chemotherapeutics that are used by oncologists to fight cancer are proapoptotic agents; however these cancers display intrinsic resistance to pro-apoptotic stimuli. In addition, metastatic cancer cells are naturally resistant to pro-apoptotic agents because they must resist anoïkis during their metastatic progression. Another major obstacle to the effective treatment of cancer is multidrug resistance (MDR), which is exhibited by many cancers and is either an intrinsic property of certain cancers or an acquired property during chronic chemotherapy. Recent published data indicate several findings: i) various cancer cell types overexpress specific ion channels compared to the respective normal cells that are derived from the same tissue and ii) inhibition of these overexpressed ion channels can be detrimental for these cancer cells. The current special issue entitled “Ion Channels and Cancers” provides an overview of this novel and exciting findings to combat cancers that are associated with dismal prognoses and reveals a large set of chemical families that could be derivatized / optimized to specifically target overexpressed ion channels in cancers. Robert Kiss and colleagues contribute a review entitled “Targeting the Na+/K+-ATPase to combat multidrug resistant (MDR) cancers and/or cancers displaying intrinsic resistance to pro-apoptotic stimuli”. This review provides an overview about the types of cancers that overexpress the Na+/K+-ATPase (NaK) and an in-depth discussion on the structure-activity-relationship (SAR) between NaK and its ligands (cardenolides versus bufadienolides) that display anticancer activities in vitro and in vivo, including in cancer patients. Christian Stock and colleagues present a review entitled “Is the multifunctional Na+/H+ exchanger isoform 1 a potential therapeutic target in cancer?”. The Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed transporter that mediates many physiological tasks in the cell. NHE1 is upregulated and/or overexpressed in a number of tumor cells. In many cases, elevated NHE1 activity correlates with increased cell motility and malignancy. In the current article, different NHE1 inhibitors are compared, and possible clinical exploitations of NHE1 inhibition are discussed. Antonio Felipe and colleagues provide a review entitled “Targeting the voltage-dependent K+ channels Kv1.3 and Kv1.5 as tumor biomarkers for cancer detection and prevention”. This article discusses potassium channels (KChs) and focuses on the largest sub-group of voltage-dependent potassium (Kv) channels. Many studies have reported the involvement of KChs in cancer progression. The current article demonstrates that the expression patterns of Kv1.3 and Kv1.5 are remodeled in cancers. Unlike Kv1.5, Kv1.3 is characterized by a selective and potent pharmacology, which may lead to specific pharmacological targeting in specific types of cancers. Luis Pardo and colleagues contribute a review entitled “Diagnostic and therapeutic approaches targeting KV10.1 open a novel therapeutic window”. KV10.1 is ectopically expressed in the majority of solid tumors. Due to its cell-surface accessibility, KV10.1 may be potentially used for tumor treatment and diagnosis. The current article provides an overview of the current data linking KV10.1 to cancer and proposes strategies that are suitable for the design of KV10.1-targeted drugs with a wider therapeutic window. Annarosa Arcangeli and colleagues enclose a review entitled “Targeting ion channels in leukemias: a new challenge for treatment”. This article focuses on Kv11.1 (also known as hERG1), a Kv channel that modulates cell adhesion to the extracellular matrix (ECM). Kv11.1 forms multiprotein membrane complexes with integrin receptors in acute myeloid leukemias (AML) and acute lymphoblastic leukemias (ALL). Blocking Kv11.1 in mice has a protective effect in acute leukemias. In ALL cells, hERG1 inhibitors abrogate the protective effect of bone marrow stromal cells and enhance the cytotoxicity of some common antileukemic drugs. The current review focuses on how ion channel modulators overcome chemoresistance in acute leukemias.....

A large proportion of cancer patients fail to respond to conventional chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli and/or the acquisition of a multidrug resistant (MDR) phenotype during chronic chemotherapy. A new angle in chemotherapeutics against these cancer types associated with dismal prognoses would be the targeting of specific ion channels and pumps over expressed by cancer cells as compared to normal cells. Several reports suggest that the alpha subunits of the Na+/K+- ATPase (referred as sodium pump from now on) could be such targets, using cardiotonic steroids (CS) including cardenolides and bufadienolides. A significant proportion of non-small-cell-lung cancers (NSCLCs), glioblastomas (GBMs), melanomas and kidney cancers overexpresses the alpha-1 subunit of the sodium pump as compared to corresponding normal tissues, while colon cancers overexpress the alpha-3 subunit. Thus, a deeper knowledge of the structure-activity relationship (SAR), in terms of CS-mediated anticancer effects, to the sodium pump alpha subunits might enable the identification of potent anticancer agents with limited cardiotoxicity. The current review provides an in depth SAR analysis with respect to cardenolide- versus bufadienolide-mediated anticancer effects. Moreover, pharmacological data from in vitro and in vivo experiments, as well as pre-clinical and clinical trials regarding cardenolides to combat cancers associated with dismal prognoses are presented.

The Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed transporter fulfilling a variety of cell physiological tasks. By importing Na+ and exporting H+, NHE1 contributes to regulatory volume increase and cytoplasmic pH homeostasis. In addition it anchors the cytoskeleton in the plasma membrane. NHE1 plays a critical role in mediating the progression of reperfusion injuries after ischemia. Moreover, it is upregulated and/or overexpressed in a number of tumour cells. In many cases an elevated NHE1 activity can be correlated with an increase in cell motility and malignancy. Consequently, NHE1 including its regulators may represent potential targets in anticancer therapy. Different NHE1 inhibitors are compared and possible clinical exploitations of NHE1 inhibition are discussed.

Potassium channels (KCh) are a diverse group of membrane proteins that participate in the control of the membrane potential. More than eighty different KCh genes have been identified, which are expressed in virtually all living cells. In addition to nerve and cardiac action potentials, these proteins are involved in a number of physiological processes, including cell volume regulation, apoptosis, immunomodulation and differentiation. Furthermore, many KCh have been reported to play a role in proliferation and cell cycle progression in mammalian cells, and an important number of studies report the involvement of KCh in cancer progression. The voltagedependent potassium (Kv) channels, in turn, form the largest family of human KCh, which comprises about 40 genes. Because Kv1.3 and Kv1.5 channels modulate proliferation of different mammalian cells, these proteins have been analyzed in a number of tumors and cancer cells. In most cancers, the expression patterns of Kv1.3 and Kv1.5 are remodeled, and in some cases, a correlation has been established between protein abundance and grade of tumor malignancy. The list of cancers evaluated is constantly growing, indicating that these proteins may be future targets for treatment. The aim of this review is to provide an updated overview of Kv1.3 and Kv1.5 channels during cancer development. Unlike Kv1.5, Kv1.3 is characterized by a very selective and potent pharmacology, which could lead to specific pharmacological targeting. Because potassium channels may play a pivotal role in tumor cell proliferation, these proteins should be taken into account when designing new cancer treatment strategies.

KV10.1 has recently become generally accepted as a promising cancer target, as it is ectopically expressed in the majority of solid tumors. Due to its cell-surface accessibility, KV10.1 has a strong potential for tumor treatment and diagnosis. Given that its mode of action is likely independent of conventional cancer pathways such as tyrosine kinases, KV10.1 opens a novel window for treating cancer. In this review we will give an overview of the current status of data linking KV10.1 to cancer, and propose techniques that could exploit KV10.1's properties for the management of cancer

Leukemias, as other cancers, bear several genetic alterations of tumor-related genes, such as point mutations, translocations, epigenetic modifications, often accompanied by gene amplification or inactivation. The identification of tumor-related genes provides considerable insight into the biology of leukemias and opens the way to more specific pharmacological treatments. These genes comprise several ion channels and pumps, as the transport mechanisms associated with volume control, proliferation and apoptosis are often altered in cancers. In leukemic cells, such changes are observed as early as the stem cell stage. Ion channels can regulate other malignant features, such as lack of differentiation, increased migratory and invasive phenotype and chemoresistance. The role of certain voltage-gated K+ channels, such as Kv11.1 (also known as hERG1) can be largely attributed to modulation of cell adhesion to the extracellular matrix (ECM). Kv11.1 exerts pleiotropic regulatory effects by forming multiprotein membrane complexes with integrin receptors in both acute myeloid leukemias (AML) and acute lymphoblastic leukemias (ALL). By recruiting growth factor and chemokine receptors, these complexes form signaling hubs that control neoplastic progression. Work in mice shows that blocking Kv11.1 has a protective effect in acute leukemias. Ion channels are most promising targets for anti-leukemic therapy, because of their accessibility from the extracellular side and the thorough understanding of their pharmacology. In ALL cells, Kv11.1 inhibitors abrogate the protective effect of bone marrow stromal cells and enhance the cytotoxicity of some common antileukemic drugs. Hence, ion channel modulators could overcome chemoresistance in acute leukemias, a major hindrance to therapeutic success.

Many studies have reported changes in potassium channel expression in many cancers and the involvement of these channels in various stages of cancer progression. By contrast, data concerning SKCa channels (small conductance calcium-activated potassium channels) have only recently become available. This review aims i) to present the structure and physiology of SKCa channels, ii) to provide an overview of published data concerning the SKCa proteins produced in tumor cells, and, whenever possible, the biological function assigned to them and iii) to review previous and novel modulators of SKCa channels. SKCa channels are activated by low concentrations of intracellular calcium and consist of homo- or heteromeric assemblies of α-subunits named SK1, SK2 and SK3. SK2-3 channels are expressed in tumors and have been assigned a biological function in cancer cells: the enhancement of cell proliferation and cell migration by hijacking the functions of SK2 and SK3 channels, respectively. Two major classes of SKCa modulators have been described: toxins (apamin) and small synthetic molecules. Most SKCa blockers are pore blockers, but some modify the calcium sensitivity of SKCa channels without interacting with the apamin binding site. In this review, we present edelfosine and ohmline as atypical anticancer agents and novel SK3 inhibitors. Edelfosine and ohmline are synthetic alkyl-lipids with structures different from all previously described SKCa modulators. They should pave the way for the development of a new class of migration-targeted anticancer agents. We believe that such blockers have potential for use in the prevention or treatment of metastasis.

Found at the outer mitochondrial membrane, the voltage-dependent anion channel, VDAC, assumes a crucial position in the cell, serving as the main interface between mitochondrial and cellular metabolisms by mediating transport of ions and metabolites. VDAC thus functions as a gatekeeper, controlling cross-talk between mitochondria and the rest of the cell. Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC to interact with proteins that mediate and regulate the integration of mitochondrial functions with other cellular activities. Here, we review current knowledge related to the roles played by VDAC in the regulation of cell life and cell death, with relation to cancer. The current concepts of altered metabolism in cancer cells are presented with specific emphasis on mitochondrial, more specifically VDAC1-bound hexokinase (HK), facilitating and promoting the high glycolytic tumor phenotype. In this respect, the up-regulation of HK expression in tumor cells and its binding to VDAC provide both a metabolic benefit and apoptosis-suppressive capacity that offers the cell a growth advantage and increases its resistance to chemotherapy. VDAC has also been recognized as a key protein in mitochondria-mediated apoptosis since it is the proposed target for the pro- and antiapoptotic Bcl-2-family of proteins, as well as due to its function in the release of apoptotic proteins located in the inter-membranal space. These and other functions point to VDAC1 as being a rational target for the development of a new generation of therapeutics.

Characteristics of CM have greatly changed over time. First-generation ionic CM have many-fold (5-7) greater osmolalities than plasma . Subsequently non ionic CM generations were looked for to reduce osmolality, and encompass nonionic monomers and nonionic dimers reaching osmolality as low as that of plasma (iso-osmolar CM) but paying however dear, as viscosity is considerably increased. Intrarenal microcirculation has its “Achilles” heel in the outer medulla, where the smallness of capillary lumen and the slackness of the capillary mesh render regular blood flow at high risk, mainly because it is the same area in which the only renal work needing oxygen is made and? Iodinated CM may exert their nephrotoxic effects in three different ways: by interfering with vascular hemodynamics, by interfering with intratubular fluid volume and composition, and by producing direct cytotoxic effects to glomerular and tubular cells due to iodine byitself. Furthermore, effects of oxygen free radical can damage glomerular cells by increasing the permeability and tubular cells impairing specific function and leading to apoptosis Although clinical nephrotoxicity has considerably improved over time, there is no evidence for an a priori superiority of a specific CM . In general , low-osmolar (2-3 times blood) and iso-osmolar (the same as blood) CM are recommended, keeping in mind that within last generation CM dimeric iso-somolar compounds reach viscosity values higher than monomeric low-osmolar compounds and hyperviscosity is a neglected mechanisms of nephrotoxicity. We suggest that CM should be classified not only by osmolality, but also by viscosity..

Ischemic stroke is the second leading cause of death and long-term disability worldwide, for which no effective therapies are available. The increasing prevalence of ischemic stroke and related health risks, combined with the lack of effective therapies, highlight the desperate need for continued research for exploring the safe and effective drugs, which favourably influence multiple pathways leading to neuroprotection and extend the benefit to a larger number of patients diagnosed with stroke. Numerous preclinical studies have reported very promising results using “neuroprotectants”, all of which have failed at clinical trials because of either safety issues or lack of efficacy. The delivery of many potentially therapeutic neuroprotectants and diagnostic compounds to specific areas of the brain is restricted by the blood-brain barrier (BBB). Nanoparticles (NPs) have colossal applications that could revolutionize the treatment of ischemic stroke. NPs can readily transmigrate across the BBB without compromising its integrity. Recent striking developments in nanotechnology have produced a great deal of nano-devices, which could be used for the treatment and neuronal regeneration following ischemic stroke. This article attempts to convey the untapped potentials of nanopharmaceuticals for the treatment of ischemic stroke. Looking towards the future, this review focuses on the potential applications of nanoparticulate systems for the delivery of therapeutic cargo into the brain for imparting neuroprotection against ischemic stroke. This review also provides an overview of targeted NPs, which are being used for imaging, neuroprotection and regeneration of ischemic brain.

Polysaccharide-K (PSK, Krestin) is one of the most commonly used medicinal mushroom extracts with a long history as an additive in cancer therapy in Asia, especially in Japan. PSK has a documented anti-tumor activity both in vitro and in vitro, in various types of cancers, including colorectal, gastric, breast, liver, pancreatic, and lung cancer. Despite PSK having been studied for about 40 years as an immune modulator and biological response modifier, the mechanisms of action by PSK have not yet been clearly and completely elucidated. This review aims to provide an up-to-date account for the effects of PSK in cancer with the hope of thereby providing an increased understanding of the molecular mechanisms of PSK and also its potential as an additive in modern cancer therapy

Phencyclidine (I) and its derivatives show such pharmacological behaviors as analgesic, anticonsulvant, anti-anxiety and antidepressant, while interacting with central nervous system. In this study, new methyl and hydroxyl derivatives of PCP were synthesized and their antinociceptive behaviors in animals were examined by measuring the number of writhing in a writhing test of visceral pain and the pain scores in Formalin test. Compared to control and PCP groups, findings in experimental groups indicated the new synthesized analogues (compounds II, III and V, 10 mg/kg) of PCP were able to produce more analgesic effects in formalin and writhing tests, especially for compound V. It was concluded that the new synthesized derivatives of PCP could substantially and respectively diminish acute and chronic pains.

Background and Purpose: Microglial activation plays an important role in neurodegenerative diseases by producing an array of proinflammatory enzymes and cytokines. Ginsenoside Rg1 (Rg1), a well-known Chinese herbal medicine, has been well recognized for its anti-inflammatory effect. This study sought to determine the anti-inflammatory effects of Rg1and its underlying mechanisms in lipopolysaccharide (LPS)-stimulated murine BV-2 microglial cells. Experimental Approach: Murine BV-2 microglial cells were treated with Rg1 (10, 20, and 40 μM) and/or LPS (1 μg·ml-1). The mRNA and protein levels of proinflammatory proteins and cytokines were analysed by RT-PCR assay and double immunofluorescence labeling, respectively. Phosphorylation levels of mitogen-activated protein kinases (MAPKs) cascades, inhibitor κB-α (IκB-α) and cyclic AMP- responsive element (CRE)-binding protein (CREB) were measured by western blot. U73122 (5 μM), a specific phospholipase C (PLC) inhibitor, was used to determine if PLC signaling pathway might be involved in Rg1's action on activated BV-2 cells. Key Results: Pretreatment with Rg1 significantly attenuated the LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and nuclear factor-κB (NF-κB) in BV-2 cells. U73122 blocked the effects of Rg1 on LPS-induced microglial activation. In addition, PLC-γ1 inhibition partially abolished the inhibitory effect of Rg1 on the phosphorylation of IκB-α, CREB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK). Conclusion and Implications: This investigation demonstrates that Rg1 significantly attenuates overactivation of microglial cells by repressing expression levels of neurotoxic proinflammatory mediators and cytokines via activation of PLC-γ1 signaling pathway.