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NAD+-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has been of significant interest for diverse therapeutic applications. In particular, it has been shown that inhibition of sirtuin 1 and 2 activities is beneficial for cancer treatment. Here, we demonstrate that the fungal metabolite eurochevalierine from the fungus Neosartorya pseudofischeri inhibits sirtuin 1 and 2 activities (IC50 about 10 µM) without affecting sirtuin 3 activity. The binding modes of the eurochevalierine for sirtuin 1 and 2 have been identified through computational docking analyses. Accordingly, this sequiterpene alkaloid induces histone H4 and α-tubulin acetylation in various cancer cell models in which it induces strong cytostatic effects without affecting significantly the viability of healthy PBMCs. Importantly, eurochevalierine targets preferentially cancer cell proliferation (selectivity factor ≫ 7), as normal human primary CD34+ stem/progenitor cells were less affected by the treatment. Finally, eurochevalierine displays suitable drug-likeness parameters and therefore represent a promising scaffold for lead molecule optimization to study the mechanism and biological roles of sirtuins and potentially a basis for development into therapeutics. [ABSTRACT FROM AUTHOR]

Cell death plays an essential role in the development of organs, homeostasis, and cancer. Apoptosis and programmed necrosis are two major types of cell death, characterized by different cell morphology and pathways. Accumulating evidence shows autophagy as a new alternative target to treat tumor resistance. Besides its well-known pro-survival role, autophagy can be a physiological cell death process linking apoptosis and programmed necrosis cell death pathways, by various molecular mediators. Here, we summarize the effects of pharmacologically active compounds as modulators of different types of cancer cell death depending on the cellular context. Indeed, current findings show that both natural and synthetic compounds regulate the interplay between apoptosis, autophagy and necroptosis stimulating common molecular mediators and sharing common organelles. In response to specific stimuli, the same death signal can cause cells to switch from one cell death modality to another depending on the cellular setting. The discovery of important interconnections between the different cell death mediators and signaling pathways, regulated by pharmacologically active compounds, presents novel opportunities for the targeted treatment of cancer. The aim of this review is to highlight the potential role of these compounds for context-specific anticancer therapy. [ABSTRACT FROM AUTHOR]

Cancer is a multifactorial disease that requires treatments able to target multiple intracellular components and signaling pathways. The natural compound, curcumin, was already described as a promising anticancer agent due to its multipotent properties and huge amount of molecular targets in vitro. Its translation to the clinic is, however, limited by its reduced solubility and bioavailability in patients. In order to overcome these pharmacokinetic deficits of curcumin, several strategies, such as the design of synthetic analogs, the combination with specific adjuvants or nano-formulations, have been developed. By taking into account the risk-benefit profile of drug combinations, as well as the knowledge about curcumin's structure-activity relationship, a new concept for the combination of curcumin with scaffolds from different natural products or components has emerged. The concept of a hybrid curcumin molecule is based on the incorporation or combination of curcumin with specific antibodies, adjuvants or other natural products already used or not in conventional chemotherapy, in one single molecule. The high diversity of such conjugations enhances the selectivity and inherent biological activities and properties, as well as the efficacy of the parental compound, with particular emphasis on improving the efficacy of curcumin for future clinical treatments. [ABSTRACT FROM AUTHOR]

Carcinogenesis is a complex and multistep process that involves the accumulation of successive transformational events driven by genetic mutations and epigenetic alterations that affect major cellular processes and pathways such as proliferation, differentiation, invasion and survival. Massive deregulation of all components of the epigenetic machinery is a hallmark of cancer. These alterations affect normal gene regulation and impede normal cellular processes including cell cycle, DNA repair, cell growth, differentiation and apoptosis. Since epigenetic alterations appear early in cancer development and represent potentially initiating events during carcinogenesis, they are considered as promising targets for anti-cancer interventions by chemopreventive and chemotherapeutic strategies using epigenetically active agents. In this field, plant-derived compounds have shown promise. Here, we will give an overview of plant-derived compounds displaying anticancer properties that interfere with the epigenetic machinery. [ABSTRACT FROM AUTHOR]

Cancer cells depend on an altered energy metabolism characterized by increased rates of both glycolysis and glutaminolysis. Accordingly, corresponding key metabolic enzymes are overexpressed or hyperactivated. As a result, this newly acquired metabolic profile determines most other cancer hallmarks including resistance to cell death. Recent findings highlighted metabolic enzymes as direct modulators of cell death pathways. Conversely, key mediators of cell death mechanisms are emerging as new binding partners of glycolytic actors; moreover, there is evidence that metabolic regulators re-localize to specific subcellular compartments or organelles to modulate various types of cell demise. The final outcome is the resistance against cell death programs. Current findings give a new meaning to metabolic pathways and allow understanding how they affect cancer-specific pathological alterations. Furthermore, they shed light on potentially targetable functions of metabolic actors to restore susceptibility of cancer cells to death. Here, we discuss an emerging interplay between cell metabolism and cell death, focusing on interactions that may offer new options of targeted therapies in cancer treatment involving more specifically hexokinases and glyceraldehyde-3-phosphate dehydrogenase. [ABSTRACT FROM AUTHOR]

Cancer remains a major public health problem in our society. The development of potent novel anti-cancer drugs selective for tumor cells is therefore still required. Deregulation of the epigenetic machinery including DNA methylation, histone modifications and non-coding RNAs is a hallmark of cancer, which provides potential new therapeutic targets. Natural products or their derivatives represent a major class of anti-cancer drugs in the arsenal available to the clinician. However, regarding epigenetically active anti-cancer agents for clinics, the oceans represent a largely untapped resource. This review focuses on marine natural compounds with epigenetic activities and their synthetic derivatives displaying anti-cancer properties including largazole, psammaplins, trichostatins and azumamides. [ABSTRACT FROM AUTHOR]

Cancer continues to be a major public health problem despite the efforts that have been made in the search for novel drugs and treatments. The current sources sought for the discovery of new molecules are plants, animals and minerals. During the past decade, the search for anticancer agents of marine origin to fight chemo-resistance has increased greatly. Each year, several novel anticancer molecules are isolated from marine organisms and represent a renewed hope for cancer therapy. The study of structure-function relationships has allowed synthesis of analogues with increased efficacy and less toxicity. In this report, we aim to review 42 compounds of marine origin and their derivatives that were published in 2011 as promising anticancer compounds. [ABSTRACT FROM AUTHOR]

Even though altered metabolism is an "old" physiological mechanism, only recently its targeting became a therapeutically interesting strategy and by now it is considered an emerging hallmark of cancer. Nevertheless, a very poor number of compounds are under investigation as potential modulators of cell metabolism. Candidate agents should display selectivity of action towards cancer cells without side effects. This ideal favorable profile would perfectly overlap the requisites of new anticancer therapies and chemopreventive strategies as well. Nature represents a still largely unexplored source of bioactive molecules with a therapeutic potential. Many of these compounds have already been characterized for their multiple anticancer activities. Many of them are absorbed with the diet and therefore possess a known profile in terms of tolerability and bioavailability compared to newly synthetized chemical compounds. The discovery of important cross-talks between mediators of the most therapeutically targeted aberrancies in cancer (i.e., cell proliferation, survival, and migration) and the metabolic machinery allows to predict the possibility that many anticancer activities ascribed to a number of natural compounds may be due, in part, to their ability of modulating metabolic pathways. In this review, we attempt an overview of what is currently known about the potential of natural compounds as modulators of cancer cell metabolism. [ABSTRACT FROM AUTHOR]

Garlic-derived organosulfur compounds including diallyl polysulfides are well known for various health-beneficial properties and recent reports even point to a potential role of diallyl polysulfides as chemopreventive and therapeutic agents in cancer treatment due to their selective antiproliferative effects. In this respect, diallyl tri- and tetrasulfide are reported as strong inducers of an early mitotic arrest and subsequent apoptosis, but the underlying molecular mechanisms and the link between these two events are not yet fully elucidated. Our data revealed that diallyl tetrasulfide acts independently of reactive oxygen species and tubulin represents one of its major cellular targets. Tubulin depolymerization prevents the formation of normal spindle microtubules, thereby leading to G2/M arrest. Here, we provide evidence that c-jun N-terminal kinase, which is activated early in response to diallyl tetrasulfide treatment, mediates multisite phosphorylation and subsequent proteolysis of the anti-apoptotic protein B-cell lymphoma 2. As the latter event occurs concomitantly with the onset of apoptosis and the chemical c-jun N-terminal kinase inhibitor SP600125 not only prevented B-cell lymphoma 2 phosphorylation and proteolysis but also apoptosis following diallyl tetrasulfide treatment, we suggest that these c-jun N-terminal kinase-mediated modulations of B-cell lymphoma 2 represent the missing link connecting early microtubule inactivation to the induction of apoptosis. [ABSTRACT FROM AUTHOR]

Although considerable progress in oncology therapeutics has been achieved in the last century, cancer remains one of major death causes in the World and for this reason, the development of novel cancer drugs remains a pressing need. Natural marine compounds represent an interesting source of novel leads with potent chemotherapeutic or chemo-preventive activities. In the last decades, structure-activity-relationship studies have led to the development of naturally-derived or semi-synthetic analogues with improved bioactivity, a simplified synthetic target or less toxicity. We aim here to review a selection of natural compounds with reported anticancer activity isolated of marine sources and their associated analogues published in 2010. [ABSTRACT FROM AUTHOR]

Despite considerable improvements in the tolerance and efficacy of novel chemotherapeutic agents, the mortality of hematological malignancies is still high due to therapy relapse, which is associated with bad prognosis. Dietary polyphenolic compounds are of growing interest as an alternative approach, especially in cancer treatment, as they have been proven to be safe and display strong antioxidant properties. Here, we provide evidence that both resveratrol and curcumin possess huge potential for application as both chemopreventive agents and anticancer drugs and might represent promising candidates for future treatment of leukemia. Both polyphenols are currently being tested in clinical trials. We describe the underlying mechanisms, but also focus on possible limitations and how they might be overcome in future clinical use - either by chemically synthesized derivatives or special formulations that improve bioavailability and pharmacokinetics. [ABSTRACT FROM AUTHOR]

Cancer-related anemia is a cytokine-mediated disorder resulting from complex interactions between tumor cells and the immune system. Overexpression of certain inflammatory cytokines results in shortened survival of red blood cells, suppression of erythroid progenitor cells, impaired iron utilization, and inadequate erythropoietin production. Numerous other factors may also contribute to the development of anemia in cancer patients. The European Cancer Anaemia Survey (ECAS) has provided the most current, comprehensive, prospectively collected data on the incidence and prevalence of anemia among cancer patients, as well as important perspectives on anemia treatment and relationship of hemoglobin and performance status. ECAS enrolled over 15,000 treated and untreated patients with various malignancies from cancer centers in 24 European countries and followed them for up to 6 months. The initial analysis of the ECAS data revealed that 39% of the total cancer patient population was anemic (hemoglobin <12.0 g/dl) at enrollment, although the rate varied according to tumor type, disease status, and cancer treatment status. Of the patients who were not anemic at enrollment and started cancer treatment during the survey, those undergoing chemotherapy – either alone or in combination with radiotherapy – had the highest incidence of anemia (63 and 42%, respectively). Low hemoglobin levels correlated with poor performance status and only 40% of patients who were anemic at some time during the survey received treatment for their anemia. These findings are noteworthy, since a growing body of clinical evidence indicates that the treatment of anemia can significantly improve patients’ quality of life and may also improve the clinical outcome. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Discusses advancement in cancer anemia management, as of January 2005. Factors that contribute to the development of anemia in cancer patients; Role of fatigue in the quality of life of cancer patients; Information on the use of recombinant human erythropoietin in anemia management.

Autophagy is involved in many cellular processes, including cell homeostasis, cell death/survival balance and differentiation. Autophagy is essential for hematopoietic stem cell survival, quiescence, activation and differentiation. The deregulation of this process is associated with numerous hematological disorders and pathologies, including cancers. Thus, the use of autophagy modulators to induce or inhibit autophagy emerges as a potential therapeutic approach for treating these diseases and could be particularly interesting for differentiation therapy of leukemia cells. This review presents therapeutic strategies and pharmacological agents in the context of hematological disorders. The pros and cons of autophagy modulators in therapy will also be discussed. [ABSTRACT FROM AUTHOR]

Abstract: Since centuries, natural compounds from plants, animals and microorganisms were used in medicinal traditions to treat various diseases without a solid scientific basis. Recent studies have shown that plants that were used or are still used in the medieval European medicine are able to provide relieve for many diseases including cancer. Here we summarize impact and effect of selected purified active natural compounds from plants used in European medieval medicinal traditions on cancer hallmarks and enabling characteristics identified by Hanahan and Weinberg. The aim of this commentary is to discuss the pharmacological effect of pure compounds originally discovered in plants with therapeutic medieval use. Whereas many reviews deal with Ayurvedic traditions and traditional Chinese medicine, to our knowledge, the molecular basis of European medieval medicinal approaches are much less documented. [Copyright &y& Elsevier]

Abstract: Apoptosis is a highly regulated mechanism by which cells undergo cell death in an active way. As one of the most challenging tasks concerning cancer is to induce apoptosis in malignant cells, researchers increasingly focus on natural products to modulate apoptotic signaling pathways. Curcumin, a natural compound isolated from the plant Curcuma longa, has chemopreventive properties, which are mainly due to its ability to arrest cell cycle and to induce apoptosis. This article reviews the main effects of curcumin on the different apoptotic signaling pathways involved in curcumin-induced apoptosis of cancer cells, including the intrinsic and extrinsic apoptosis pathways, the NF-κB-mediated pathway as well as the PI3K/Akt signaling pathway. This review also focuses on the sensitization of cells to TRAIL-induced apoptosis after curcumin treatment and shows that curcumin enhances the capacity to induce cell death of different chemotherapeutical drugs. [Copyright &y& Elsevier]

Cell death is an important physiological regulator during development, tissue homeostasis and stress response but it is also a protective tumor suppressive mechanism. Tumor cells almost universally acquire the ability to evade cell death pathways that in normal cells act as a protective mechanism to remove damaged cells. As a result, a population of death-resistant cells with accumulating genetic and epigenetic abnormalities contributes to malignant transformation. Any alteration of the homeostatic balance between survival and death is therefore a critical factor in carcinogenesis. Several forms of cell death exist and cross talk among them is emerging; however, we still miss many molecular details. It becomes essential to revisit the role of each type of cell death to understand interconnections existing between different cell death pathways as well as the network of their mediators to eventually develop new effective strategies to kill cancer cells. More specifically, new therapies based on compounds selectively triggering apoptosis, necrosis or autophagy recently became both appealing and challenging. Despite the rather clear classification of the different cell death modalities according to morphological criteria and the attempt to describe them with distinct signaling pathways, the reality reveals a complex interplay between apoptosis, regulated necrosis and autophagy involving a heterogeneous mix of molecular mediators. Nature, presenting an almost endless plenitude of bioactive scaffolds, can efficiently contribute compounds that allow deciphering the intricate pathways of cell death pathways and thus eventually contribute to selectively target cancer-type specific pathways in an attempt to personalize cancer patient treatment depending on cancer death pathway specificities. The aim of this review is to provide first an overview of molecular cell death specificities and to highlight how compounds of natural origins, with or without hemisynthetic modifications, target unique thanatotic molecular constellations. [ABSTRACT FROM AUTHOR]

Increased proliferation rates as well as resistance to apoptosis are considered major obstacles for the treatment of patients with chronic myelogenous leukemia (CML), thus highlighting the need for novel therapeutic approaches. Since senescence has been recognized as a physiological barrier against tumorigenesis, senescence-based therapy could represent a new strategy against CML. DNA demethylating agent 5-aza-2'-deoxycytidine (DAC) was reported to induce cellular senescence but underlying mechanisms remain to be elucidated. Here, we report that exposure to DAC triggers senescence in chronic leukemia cell lines as evidenced by increased senescence-associated β-galactosidase activity and lysosomal mass, accompanied by an up-regulation of cell cycle-related genes. We provide evidence that DAC is able to decrease telomere length, to reduce telomerase activity and to decrease human telomerase reverse transcriptase (hTERT) expression through decreased binding of c-myc to the hTERT promoter. Altogether, our results reveal the role of c-myc in telomere-dependent DAC-induced senescence and therefore provide new clues for improving chronic human leukemia treatments. [ABSTRACT FROM AUTHOR]

Abstract: Traditional pharmacopeia is strongly involved in the continuous search for the well being of African populations. The World Health Organization (WHO) estimates that 80% of the population of developing countries relies on traditional medicine for their primary care needs. Medicinal plants are the major resource of this folk medicine where several species are used for the treatment of diseases with an inflammatory and/or infectious component as it is the case of old wounds, skin diseases and malfunctions affecting internal organs such as liver, lung, prostate and kidney. Many of these pathologies described by practitioners of traditional medicine have similarities with certain cancers, but the lack of training of many of these healers does not allow them to establish a link with cancer. However, ethnobotanical and ethnopharmacological surveys conducted by several researchers allowed to identify plants of interest for cancer treatment. Most scientific investigations on these plants demonstrated an anti-inflammatory or antioxidant effect, and sometimes, antiproliferative and cytotoxic activities against cancer cells were reported as well. The emergence of resistance to cancer chemotherapy has forced researchers to turn to natural products of plant and marine origin. In the West African sub-region, research on natural anti-cancer molecules is still in its infancy stage because of very limited financial resources and the scarcity of adequate technical facilities. However, several plants were investigated for their anticancer properties through north–south or south–south partnerships. In this review, we will review the role of West African traditional pharmacopeia in cancer treatment as well as medicinal plants with anti-cancer properties. [Copyright &y& Elsevier]