Sesquiterpenes: natural products that decrease cancer growth

Despite recent advances in our understanding of the biological processes leading to the development of cancer, there is still a need for new and effective agents to help bring this disease under control. One of the oldest and most effective strategies for developing new chemotherapeutics is the isolation and evaluation of chemicals of natural origin. The importance of natural products for drug discovery has been impressive: One has to only look at the number of clinically active drugs that are used in cancer therapy to see how many are either natural products or are based on natural products. It is also apparent that materials from natural sources are excellent probes (indicators) for cellular targets that, when modulated, may have a deleterious effect upon the survival or proliferation of tumor cells. And the search goes on. Sesquiterpenes are a class of naturally occurring molecules that have demonstrated therapeutic potential in decreasing the progression of cancer. These molecules are 15-carbon isoprenoid compounds that are typically found in plants and marine life. Although this class of compounds has frequently provided encouraging leads for chemotherapeutics, they have not been evaluated as potential anticancer agents. In this review, we provide a current overview of sesquiterpenoids that have potential as anticancer agents.     

Tumor stem cell niches: a new functional framework for the action of anticancer drugs

Newer treatments of advanced human cancer increasingly rely on combinations of drugs that have quite different actions yet unexpectedly potentiate each other's effects. Recent research in stem cell biology suggests a model for tumors in which tumor growth is governed by the generation of cells from tumor cell niches rather than from the population as a whole. Each niche contains a population of tumor stem cells supported by a closely associated vascular bed comprising mesenchyme-derived cells and an extracellular matrix. Division of tumor stem cells is asymmetric in the sense that some daughter cells are always retained within the niche while others leave the niche to proliferate further and eventually die. One important potential difference between normal and tumor stem cell niches is that while most normal stem cells are in a non-proliferating or G(0)-state, tumor stem cells are continuously in cycle. Combinations of cytotoxic drugs and antagonists of survival factors to reduce the stem cell population may require the addition of vascular disrupting agents to compromise the function of the tumor cell niche. As well as providing opportunities for new drug discovery, this model of tumor growth also presents challenges as to how the contributions of individual drugs in a combination might be assessed in individual patients.     

Modulation of k-Ras signaling by natural products

Ras proteins regulate diverse cellular pathways that are important in the growth and spread of malignancies, including cell proliferation, cell cycle regulation, cell survival, angiogenesis and cell migration. These proteins lack the conventional transmembrane or hydrophobic domain typical of membrane associated proteins. Being small and hydrophilic in nature, these proteins undergo four-stage post-translational lipid modifications viz. prenylation, AAX proteolysis, carboxymethylation and palmitoylation for membrane localization which is important for their function. Therefore, enzymes involved in these modifications viz. farnesyl transferase (FTase), geranylgeranyl transferase-I (GGTase-I), geranylgeranyl transferase-II (GGTase-II), Ras converting enzyme-1 (Rce-1) and isoprenyl cysteine methyl transferase (ICMT) are emerging as potential therapeutic targets for the discovery of newer anticancer therapeutics. Several natural products have shown modulation of these post-translational enzymes. In the present review, natural products isolated from terrestrial as well as marine sources showing ability to modulate these k-Ras post-translational targets and their promise as potential anticancer agents have been discussed. A total of 157 natural products with 141 corresponding references have been covered.     

Hypoxic cells as specific drug targets for chemotherapy

Hypoxic cells exist in solid tumors in regions of poor vascularity and are likely to be exposed to insufficient concentrations of chemotherapeutic agents. Furthermore, because these cells may be cycling very slowly or may be quiescent, they may not be sensitive to agents which are most active in proliferating cells. Under conditions of reoxygenation, hypoxic cells which have survived therapy may re-enter the cell cycle and repopulate a tumor which had shown responsiveness. Three classes of agents have recently been shown to be selectively toxic to hypoxic cells in vitro. For some of these agents, combinations of hypoxic cell-selective drugs and agents with selectivity for well oxygenated cells have demonstrated improved tumor cell kill in solid transplantable rodent tumor systems. The selectivity of these classes of drugs apparently stems from enhanced activation of the drug under hypoxic conditions. Although all of these drugs exhibit selectivity, the wide divergence in the therapeutic ratios for the individual agents suggests that it may be possible to develop newer agents that are highly toxic to hypoxic cells with little toxicity for normal tissues.     

Biomaterials for stem cell differentiation

The promise of cellular therapy lies in the repair of damaged organs and tissues in vivo as well as generating tissue constructs in vitro for subsequent transplantation. Unfortunately, the lack of available donor cell sources limits its ultimate clinical applicability. Stem cells are a natural choice for cell therapy due to their pluripotent nature and self-renewal capacity. Creating reserves of undifferentiated stem cells and subsequently driving their differentiation to a lineage of choice in an efficient and scalable manner is critical for the ultimate clinical success of cellular therapeutics. In recent years, a variety of biomaterials have been incorporated in stem cell cultures, primarily to provide a conducive microenvironment for their growth and differentiation and to ultimately mimic the stem cell niche. In this review, we examine applications of natural and synthetic materials, their modifications as well as various culture conditions for maintenance and lineage-specific differentiation of embryonic and adult stem cells.     

Antineoplastic agents from natural sources: achievements and future directions

The influence of natural products upon anticancer drug discovery and design cannot be overestimated. Approximately 60% of all drugs now in clinical trials for the multiplicity of cancers are either natural products, compounds derived from natural products, contain pharmacophores derived from active natural products or are 'old drugs in new clothes', where (modified) natural products are attached to targeting systems. This review covers those materials that the authors are aware of as being in clinical trials through early 2000 and demonstrates how, even today, in the presence of massive numbers of agents from combinatorial libraries, the compounds produced by 'Mother Nature' are still in the forefront of cancer chemotherapeutics as sources of active chemotypes.     

RPF101, a new capsaicin-like analogue,disrupts the microtubule network accompanied by arrest in the G2/M phase,inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cells

Breast cancer is the world's leading cause of death among women. This situation imposes an urgent development of more selective and less toxic agents. The use of natural molecular fingerprints as sources for new bioactive chemical entities has proven to be a quite promising and efficient method. Capsaicin, which is the primary pungent compound in red peppers, was reported to selectively inhibit the growth of a variety tumor cell lines. Here, we report for the first time a novel synthetic capsaicin-like analogue, RPF101, which presents a high antitumor activity on MCF-7 cell line, inducing arrest of the cell cycle at the G2/M phase through a disruption of the microtubule network. Furthermore, it causes cellular morphologic changes characteristic of apoptosis and a decrease of Δψm. Molecular modeling studies corroborated the biological findings and suggested that RPF101, besides being a more reactive molecule towards its target, may also present a better pharmacokinetic profile than capsaicin. All these findings support the fact that RPF101 is a promising anticancer agent.     

Antineoplastic agents from natural sources: achievements and future directions

The influence of natural products upon anticancer drug discovery and design cannot be overestimated. Approximately 60% of all drugs now in clinical trials for the multiplicity of cancers are either natural products, compounds derived from natural products, contain pharmacophores derived from active natural products or are ‘old drugs in new clothes’, where (modified) natural products are attached to targeting systems. This review covers those materials that the authors are aware of as being in clinical trials through early 2000 and demonstrates how, even today, in the presence of massive numbers of agents from combinatorial libraries, the compounds produced by ‘Mother Nature’ are still in the forefront of cancer chemotherapeutics as sources of active chemotypes.     

Natural products as anti-invasive and anti-metastatic agents

Invasion and metastasis, the hallmark of malignant tumor, is the main reason for the clinical death of most cancer patients. Tumor invasion and metastasis are complex, multi-step biochemical processes, which involve cell detachment, invasion, migration, intravasation and circulation, implantation, angiogenesis and proliferation. Therefore, how to prevent tumor metastasis has been the biggest challenge in cancer chemotherapy. In recent years, many natural products have been found to have anti-invasive and anti-metastatic activities. In this paper, these natural compounds are classified as polyphenols, terpenoids, alkaloids, steroids and saponins, saccharides, macrolides, amides and others, their anti-invasive and anti-metastatic activities as well as their biological targets are reviewed.     

Signal Transduction Events Elicited by Natural Products that Function as Cancer Chemopreventive Agents

Cancer chemoprevention is a rapidly emerging paradigm for slowing, stopping or reversing the carcinogenic process. A multiplicity of biological mechanisms, functioning as complex interactions of gene products and regulatory pathways, are stimulated or inhibited by cancer chemopreventive agents. Several natural products and dietary components have been shown to function as chemopreventive agents. Screening chemical libraries of natural products for properties associated with cancer chemoprevention provides important insight into structural motifs driving rational design of more effective agents. In this review, the signal transduction pathways that are modulated by chemopreventive natural products are summarized. The activation of several signal transduction pathways triggered by polyphenolic antioxidants, flavonoids, retinoids, phytoestrogens and isothiocyanates are illustrated. These natural products may disrupt many signaling pathways, including transduction of cell surface (epidermal growth factor) or nuclear (estrogen) receptors via inhibition of their associated tyrosine kinase activities that regulate mitogenic signaling cascades (e.g., c-Raf-1). Alternatively, cytoprotective signal transduction pathways may be activated in a concentration- and time-dependent manner. The consequences of the modulation of signal transduction pathways by administration of these cancer chemopreventive compounds, singly or in combination, are the inhibition of cell cycle activating cascades and induction of cell survival / protection genes. Understanding the activation of signal transduction events elicited by various drugs and chemicals may yield insights into the regulation of the expression of genes coordinating cell proliferation, death, as well as, drug metabolizing and other cytoprotective enzymes. Monitoring the activation or inhibition of these pathways may serve as endpoints for rapid screening of effective cancer chemopreventive agents.     

In vitro modulation of telomerase activity, telomere length and cell cycle in MKN45 cells by verbascoside

Screening of natural products with anti-tumor activity as telomerase inhibitor is a new subject in the field of tumor therapy. Using telomerase PCR ELISA, telomere DNA hybridization and flow cytometry analysis, the effects of verbascoside, a phenylpropanoid glucoside extracted from Pedicularis striata Pall, on telomerase activity, telomere length and cell cycle of human gastric carcinoma cells MKN45 was examined in vitro. After being treated with a 50 % inhibition concentration of verbascoside (17.8 microg/ml), telomerase activity in the cells was significantly inhibited but not in the cellular supernatant, the average telomere length became remarkably short, and the sub-G0 /G1 peak and G2/M arrest were also displayed when compared to the control cells. These results suggest that verbascoside mediated-cell differentiation and apoptosis may be affected by telomere-telomerase-cell cycle dependent modulation. Thus, the antitumor mechanism of verbascoside is demonstrated once more by its inhibiting effect on telomerase activity in tumor cells, and the telomerase assay may provide a valuable screening method for antitumor activity of natural products.     

Natural products of dietary origin as lead compounds in virtual screening and drug design

Natural products have been found to be useful in the treatment of several diseases across the ages. In this article, we review the use of natural products, obtained from dietary sources, as lead compounds in developing novel therapeutic agents. These compounds have shown tremendous promise in the prevention and as well as treatment of a variety of chronic ailments. In addition, to being patentable and biocompatible, these compounds are a rich source of novel scaffolds to invigorate the pipelines of the pharmaceutical industry. In this communication, we also focus on studies which show how natural products have proved useful as lead compounds in virtual screening and structure-based drug design programs. Natural dietary constituents, such as resveratrol, curcumin and caffeine as well as other compounds, are discussed to illustrate this approach.     

Mechanism targeted discovery of antitumor marine natural products

Antitumor drug discovery programs aim to identify chemical entities for use in the treatment of cancer. Many strategies have been used to achieve this objective. Natural products have always played a major role in anticancer medicine and the unique metabolites produced by marine organisms have increasingly become major players in antitumor drug discovery. Rapid advances have occurred in the understanding of tumor biology and molecular medicine. New insights into mechanisms responsible for neoplastic disease are significantly changing the general philosophical approach towards cancer treatment. Recently identified molecular targets have created exciting new means for disrupting tumor-specific cell signaling, cell division, energy metabolism, gene expression, drug resistance and blood supply. Such tumor-specific treatments could someday decrease our reliance on traditional cytotoxicity-based chemotherapy and provide new less toxic treatment options with significantly fewer side effects. Novel molecular targets and state-of-the-art, molecular mechanism-based screening methods have revitalized antitumor research and these changes are becoming an ever-increasing component of modern antitumor marine natural products research. This review describes marine natural products identified using tumor-specific mechanism-based assays for regulators of angiogenesis, apoptosis, cell cycle, macromolecule synthesis, mitochondrial respiration, mitosis, multidrug efflux and signal transduction. Special emphasis is placed on natural products directly discovered using molecular mechanism-based screening.     

The modification of natural products for medical use

Drug innovation is characterized by painstaking molecular-level syntheses and modifications as the basic components of research and development. Similarly, natural products are chemically tailored and modified based upon their structural and biological properties. To some extent, the modification of natural products is quite different from de novo structure-based drug discovery. This review describes the general strategies and principles for the modification of natural products to drugs, as illustrated by several successful medicines that originated from natural products.     

Discovery and utilization of marine leading compounds in tumor immunity

OBJECTIVE Anti-PD therapyhas become the backbone of cancer immunotherapy. However, many patients with cancer fail to respond to compounds that target the PD-1 and PD-L1 interaction. Given the significance of modulating PD-L1 expression in anti-PD therapy,we screened in-house marine natural products library based on high throughput flow cytometry platform. METHODS We evaluated total 616 in-house marine natural products by established flow cytometry platform and identified the mechanism that how "hit" upregulate the expression of PD-L1. Also, we investigated the in vivo tumor associated immunity response. RESULT We identified C-210 could significantly upregulate the PD-L1 expression and further studies have suggested that such interesting effect was due to the activation of MAPK pathway.Moreover, we observed that the pharmacological effect of C-210 increased levels of cytotoxic Tlymphocytes and synergized with anti-PD-L1 therapy in murine models.CONCLUSION High throughput flow cytometry screening system can help to found the leading compounds that potentially affect tumor immunity within the marine natural products.     

Ubiquitination in Rho signaling

The Rho family small GTPases of the Ras superfamily play key roles in regulating diverse signaling pathways that control a myriad of fundamental cellular processes such as cytoskeletal dynamics, cell cycle progression, gene expression, cell polarity, migration and cell transformation. The Rho GTPases cycle between an active GTP-bound and an inactive GDP-bound form, which is controlled by many regulators including GEFs, GAPs and GDIs. Recent studies have revealed a new layer of regulation for Rho GTPases, indicating that several members of the Rho family of small GTPases including RhoA, Rac1, and RhoBTB, as well as the Ras family member Rap1B, are also regulated by the ubiquitin-proteasome pathway, which plays important roles in controlling cell polarity, migration, cell transformation and actin dynamics. Importantly, regulators for Rho GTP-GDP cycling such as RhoGDI and Rho-GEF ECT2 were also found to be modulated by the ubiquitin pathway. In this review, we focus on how ubiquitin signaling guides the fate and function of Rho GTPases and their regulators, especially how the E3 ubiquitin ligase Smurf1 regulates cell polarity and motility through targeting RhoA for ubiquitination and degradation.     

Geldanamycin, radicicol, and chimeric inhibitors of the Hsp90 N-terminal ATP binding site

Natural products have continued to drive the development of new chemotherapeutics and elucidation of new biological targets for the treatment of disease. Since Whitesell and Neckers' original discovery that geldanamycin does not directly inhibit v-Src, but instead manifests its biological activity through inhibition of the Hsp90 molecular chaperone, additional natural products and natural product derivatives have been identified and developed to inhibit the Hsp90 protein folding machinery. 17-AAG, a geldanamycin analogue, is currently in clinical trials for the treatment of several types of cancer. Recent work has produced improved radicicol analogues that show promising Hsp90 inhibitory activity in vitro. In addition, chimeric molecules of these two natural products are active in vitro and represent a novel class of Hsp90 inhibitors for cancer treatment. In addition to their chemotherapeutic uses, natural product inhibitors and their derivatives have been utilized to probe the biological mechanisms by which Hsp90 inhibition regulates tumor cell growth. As a consequence of these studies, the molecular chaperones have emerged as an exciting new class of therapeutic targets. This review will highlight the utility of the natural products, geldanamycin and radicicol, as well as improved analogues and the activities exhibited by these compounds against various cancer cell lines.     

Development of novel types of biologically active compounds based on natural products and biomolecules

Enzyme inhibitors have been utilized as useful tools for elucidating the function and structure of specific enzymes and for cell biology studies. Recently, chemical screening from natural sources and compound libraries has led to the rapid discovery of enzyme inhibitors. To create more useful inhibitors with high enzyme selectivity, and molecular probes for analyzing the precise mode of actions for enzymes, synthetic approaches based on natural products and bio-molecules are considered to have an important role in medicinal chemistry and chemical biology. In this review, the "focused library approach" for the development of inhibitors and modulators for enzymes related to protein phosphorylations and de-phosphorylations was introduced. As protein kinase C modulators, we constructed a focused library with the conformationally-constrained 1,2-diacylglycerol (DAG) motif as the core structure. Among the synthesized compounds, we found some characteristic molecules with different binding affinity to the C1 domain and activation ability for PKCα. As inhibitors for the dual-specificity protein phosphatase VHR, the neutral phosphate-mimicking core structure was designed based on natural product RK-682. Among the derivatives of the constructed focused library, including the neutral core structure stated above, we found the selective inhibitor for VHR, which showed cell cycle arresting activity for NIH3T3 cells and inhibitory activity for the de-phosphorylation of ERK and JNK.     

Natural peroxy anticancer agents

Present review describes research on novel natural anticancer agents isolated from terrestrial and marine sources. More than 120 cytotoxic anticancer compounds have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to Natural Cancer Institute for further in vivo evaluation. Intensive searches for new classes of pharmacologically potent agents produced by terrestrial and marine organisms have resulted in the discovery of dozens of compounds possessing high cytotoxic activities. However, only a limited number of them have been tested in pre-clinical and clinical trials. One of the reasons is a limited supply of the active ingredients from the natural sources. However, the pre-clinical and clinical development of many terrestrial and/or marine-derived natural products into pharmaceuticals is often hampered by a limited supply from the natural source. Total synthesis is of vital importance in these situations, allowing for the production of useful quantities of the target compound for further biological evaluation. With computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of terrestrial and marine peroxides as an important source of leads for drug discovery.