Current Drug Targets - Volume 13, Issue 8, 2012

Cancer cells produce high levels of reactive oxygen species (ROS) that lead to a state of increased basal oxidative stress. Since this state of oxidative stress makes cancer cells vulnerable to agents that further augment ROS levels, the use of pro-oxidant agents is emerging as an exciting strategy to selectively target tumor cells. Natural products have provided a significant contribution to the development of several drugs currently used in cancer chemotherapy. Although many natural products are known to affect the redox state of the cell, most studies on these compounds have focused on their antioxidant activity instead of on their pro-oxidant properties. This article provides an overview of natural products with pro-oxidant and anticancer activities, with special focus on plant secondary metabolites, and discusses their possible use as cancer chemotherapeutic agents.

Small molecules that modulate histone acetylation by targeting key enzymes mediating this posttranslational modification – histone acetyltransferases and histone deacetylases – are validated chemotherapeutic agents for the treatment of cancer. This area of research has seen a rapid increase in interest in the past decade, with the structurally diverse natural products-derived compounds at its forefront. These secondary metabolites from various biological sources target this epigenetic modification through distinct mechanisms of enzyme regulation by utilizing a diverse array of pharmacophores. We review the discovery of these compounds and discuss their modes of inhibition together with their downstream biological effects.

Marine Cyanobacteria have raised growing attention as sources of bioactive “secondary metabolites” that originate from mixed biosynthetic pathways. Some of these molecules exhibit antitumour activities with unique mechanism of action. This mini-review focuses specifically on new molecules that may act as leads for novel drug development.

The cancer stem cell (CSC) hypothesis presents a fundamentally different paradigm for cancer treatment. CSCs reflect a small fraction of tumor initiating cells capable of sustained self-renewal and differentiation to form the heterogeneous tumor bulk. In order to cure cancer, it is necessary to eliminate cancer stem cells in addition to differentiated cancer cells to decrease metastasis, reduce recurrence, and improve patient survival. In this article, we review cancer stem cell signaling pathways, including Wnt, Hedgehog, and Notch, as well as interactions of CSCs with the tumor microenvironment. We also review methods to isolate CSCs and demonstrate therapeutic efficacy of natural products to modulate these signaling pathways for eliminating CSCs.

Vinorelbine is an antimitotic anticancer agent and its main mechanism of action is related to the inhibition of microtubule dynamics leading to a mitotic arrest and cell death. Vinorelbine, as a microtubule destabilizing agent, stimulates microtubule depolymerization and mitotic spindle destruction at high concentration whereas at lower concentrations, it is able to block mitotic progression. Its main targets are tubulin and microtubules. Vinorelbine binds to β-tubulin subunits at Vinca-binding domain near the positive end of microtubules. The rapid and reversible binding by Vinorelbine to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself which plays a key role in the kinetics of microtubule stabilization. This binding significantly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the duration which microtubules spend in an attenuated state. This helps in proper assembly of the mitotic spindle and hence reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. The aim of this review is to examine the mechanism of the inhibition of cell proliferation by Vinorelbine and its efficacy in breast cancer patients in phase II studies.

One of the major issues facing anticancer research relies on the intrinsic inability of tumor cells to undergo apoptosis. Additionally, the development of cancer resistance to standard therapy and the great heterogeneity associated with frequent mutations and epigenetic changes make an ever increasing challenge to achieve treatment success. Thus, novel therapeutic approaches to induce cancer demise must be explored. Compelling evidence has shown the ability of naturally-occurring compounds to modulate signal transduction pathways, apoptosis and cell cycle progression, supporting their relevance to anticancer drug discovery. Moreover, millions of years of biological selection have led to an unlimited repertoire of chemical structures unmatched by any synthetic combinatorial library and recent advances in the fields of chemistry and biology are uncovering this still underexplored source of new promising natural agents, opening novel perspectives for the development of alternative strategies to fight cancer. This review presents the current status of natural products in modern oncology, illustrating the importance of some old and new agents, such as antimitotics and apoptosis inducers, as candidates of pharmacological interest in drug development and/or as chemical tools for the elucidation, as well as targeting, of deregulated cancer signaling pathways. Finally, some aspects of chemical modifications done in natural products core aiming to improve their activity and/or effectiveness will be discussed.

3-(4'-Geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid (4'-geranyloxyferulic acid, GOFA) is a secondary metabolite biosynthetically related to ferulic acid in which a geranyl chain is attached to the phenolic group, extracted in 1966 from Acronychia baueri Schott (Fam. Rutaceae). In the last decade the pharmacological properties of the title compound began to be characterized, revealing its good activity as anti-inflammatory and dietary feeding cancer chemopreventive agent. The aim of this review is to examine in detail the recently reported properties of 4'-geranyloxyferulic acid from a chemical and pharmacological point of view, including the recent acquisition about its mechanism of action.

This review focuses on TNF-related apoptosis-inducing ligand (TRAIL), also called Apo2 ligand, a protein belonging to the TNF superfamily. TRAIL can be found either in its transmembrane or circulating form, and its mostly studied peripheral effect is the induction of cellular apoptosis. Here, we discuss the evidences supporting the use of TRAIL as biomarker of cardiovascular diseases as well as the evidences showing the potential beneficial therapeutic effects of TRAIL on cardiovascular diseases and diabetes.

The recent finding that acetylcholinesterase (AChE) colocalizes with β-amyloid (Aβ), promotes and accelerates Aβ aggregation has renewed an intense interest in developing new multitarget AChE inhibitors as potential diseasemodifying drugs for Alzheimer's therapy. In this review, we first briefly discuss the linkage and complex interplay among the three characteristic hallmarks of Alzheimer's disease (AD): amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and cholinergic hypofunction. We then review the recent studies on the four marketed cholinesterase inhibitors in term of their multiple activities, potential disease-modifying effects, and the underlying mechanisms of these actions. We finally focus on a new emerging strategy or multitarget AChE inhibitors as effective drugs for AD therapy. We explore some examples of multitarget ChE inhibitors developed in our own and other laboratories, which were purposely designed to address multiple AD etiological targets. These new AChE inhibitors hold great promise for improving cognitive functions in AD patients, slowing down the disease progression, as well as treating behavior problems related to AD.

Leukotrienes are important mediators of pain and inflammation and they are produced in the arachidonic acid pathway via 5-lipoxygenase. They have been shown to have important roles in pyresis following antigen attack and in aspirin- intolerant asthma. They promote inflammation processes including eosinophil migration, increase in vascular permeability and bronchoconstriction. Hence, targeting the enzymes involved in the synthesis of these mediators can lead to the development of novel anti-inflammatory drugs. However, no drugs have yet been developed targeting leukotriene C4 synthase, a key enzyme leading to the synthesis of cysteinyl leukotrienes. The recent elucidation of its crystal structure now opens up the possibility of drugs against it. The inhibitors developed for this enzyme until now and the structural features responsible for their activity are discussed in this review. This understanding could lead to the design of new chemical entities.