Marc Schumacher

Gold from the sea: Marine compounds as inhibitors of the hallmarks of cancer

Cancer is one of the most deadly diseases in the world. Although advances in the field of chemo-preventive and therapeutic medicine have been made regularly over the last ten years, the search for novel anticancer treatments continues. In this field, the marine environment, with its rich variety of organisms, is a largely untapped source of novel compounds with potent antitumor activity. Although many reviews of marine anticancer compounds have been published, we focus here on selected marine compounds that act on the six hallmarks of cancer presented namely self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replication, sustained angiogenesis and tissue invasion and metastasis.

Antioxidant and anti-proliferative properties of lycopene

Abstract The recent search for new anti-cancer drugs focuses more on natural compounds from the regular human diet because these compounds rarely exhibit severe side-effects yet efficiently act on a wide range of molecular targets involved in carcinogenesis. One promising compound, which is now being tested in clinical studies, is the tomato-derived carotenoid lycopene. This review summarizes the current knowledge about the cellular action of lycopene and presents the molecular targets responsible for its remarkable chemopreventive and anti-proliferative activity. Its antioxidant effects include a considerable reactive oxygen species (ROS) scavenging activity, which allows lycopene to prevent lipid peroxidation and DNA damage. Simultaneously, lycopene induces enzymes of the cellular antioxidant defense systems by activating the antioxidant response element transcription system. As another chemopreventive strategy, lycopene increases gap junctional communication, which is suppressed during carcinogenesis. This review focuses also on the synergistic effects of lycopene with other natural antioxidants that might be important for its future application in anti-cancer treatment. Lastly, this review provides evidence for the biological activity of some oxidized lycopene metabolites, which seem to be partially responsible for the strong and manifold anti-cancer potential of lycopene.

Dermacozines, a new phenazine family from deep-sea dermacocci isolated from a Mariana Trench sediment.

Dermacoccus abyssi sp. nov., strains MT1.1 and MT1.2 are actinomycetes isolated from Mariana Trench sediment at a depth of 10 898 m. Fermentation using ISP2 and 410 media, respectively, lead to production of seven new oxidized and reduced phenazine-type pigments, dermacozines A-G (1-7), together with the known phenazine-1-carboxylic acid (8) and phenazine-1,6-dicarboxylic acid (9). Extensive use was made of 1D and 2D-NMR data, and high resolution MS to determine the structures of the compounds. To confirm the structure of the most complex pentacyclic analogue (5) we made use of electronic structure calculations to compare experimental and theoretical UV-Vis spectra, which confirmed a novel structural class of phenazine derivatives, the dermacozines. The absolute stereochemistry of dermacozine D (4) was determined as S by a combination of CD spectroscopy and electronic structure calculations. Dermacozines F (6) and G (7) exhibited moderate cytotoxic activity against leukaemia cell line K562 with IC(50) values of 9 and 7 microM, respectively, while the highest radical scavenger activity was observed for dermacozine C (3) with an IC(50) value of 8.4 microM.

Synthesis and cytotoxic potential of heterocyclic cyclohexanone analogues of curcumin

A series of 18 heterocyclic cyclohexanone analogues of curcumin have been synthesised and screened for their activity in both adherent and non-adherent cancer cell models. Cytotoxicity towards MBA-MB-231 breast cancer cells, as well as ability to inhibit NF-kappaB transactivation in non-adherent K562 leukemia cells were investigated. Three of these analogues 3,5-bis(pyridine-4-yl)-1-methylpiperidin-4-one B1, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidin-4-one B10, and 8-methyl-2,4-bis((pyridine-4-yl)methylene)-8-aza-bicyclo[3.2.1]octan-3-one C1 showed potent cytotoxicity towards MBA-MB-231, MDA-MB-468, and SkBr3 cell lines with EC50 values below 1 microM and inhibition of NF-kappaB activation below 7.5 microM. The lead drug candidate, B10, was also able to cause 43% of MDA-MB-231 cells to undergo apoptosis after 18 h. This level of activity warrants further investigation for the treatment of ER-negative breast cancer and/or chronic myelogenous leukemia as prototypical cellular models for solid and liquid tumors.

UNBS1450, a steroid cardiac glycoside inducing apoptotic cell death in human leukemia cells.

Cardiac steroids are used to treat various diseases including congestive heart failure and cancer. The aim of this study was to investigate the anti-leukemic activity of UNBS1450, a hemi-synthetic cardenolide belonging to the cardiac steroid glycoside family. Here, we report that, at low nanomolar concentrations, UNBS1450 induces apoptotic cell death. Subsequently, we have investigated the molecular mechanisms leading to apoptosis activation. Our results show that UNBS1450 inhibits NF-κB transactivation and triggers apoptosis by cleavage of pro-caspases 8, 9 and 3/7, by decreasing expression of anti-apoptotic Mcl-1 and by recruitment of pro-apoptotic Bak and Bax protein eventually resulting in cell death.

Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through proteasome inhibition and induces apoptotic cell death

In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNFalpha-treated cells and which genes display an interaction effect between heteronemin and TNFalpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappaB (NF-kappaB) signaling cascade. We confirmed in silico experiments regarding NF-kappaB inhibition by reporter gene analysis, electrophoretic mobility shift analysis and I-kappaB degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypsin-like proteasome activity at an IC(50) of 0.4 microM. Concomitant to the inhibition of the NF-kappaB pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by annexin V-FITC/propidium iodide-staining, nuclear morphology analysis, pro-caspase-3, -8 and -9 and poly(ADP-ribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, results show that this compound has potential as anti-inflammatory and anti-cancer agent.

ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis

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.

Traditional West African pharmacopeia, plants and derived compounds for cancer therapy

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.

Anti-inflammatory, pro-apoptotic, and anti-proliferative effects of a methanolic neem (Azadirachta indica) leaf extract are mediated via modulation of the nuclear factor-κB pathway.

Azadirachta indica (neem tree) is used in traditional Indian medicine for its pharmacological properties including cancer prevention and treatment. Here, we studied a neem extract’s anti-inflammatory potential via the nuclear factor-κB (NF-κB) signaling pathway, linked to cancer, inflammation, and apoptosis. Cultured human leukemia cells were treated with a methanolic neem leaf extract with or without tumor necrosis factor (TNF)-α stimulation. Inhibition of NF-κB activity was demonstrated by luciferase assay and electrophoretic mobility shift assay (EMSA). Inhibition of viability by neem extracts was assessed by luminescent assays. Western blot analysis allowed assessing the inhibitory effect of the neem extract on TNF-α-induced degradation of inhibitor of κB (IκB) and nuclear translocation of the NF-κB p50/p65 heterodimer. Inhibition of IκB kinase (IKK) activity was shown as well as the effect of neem extract on the induction of apoptotic cell death mechanisms by nuclear fragmentation analysis and flow cytometry analysis. In conclusion, our data provide evidence for a strong effect of the neem extract on pro-inflammatory cell signaling and apoptotic cell death mechanisms, contributing to a better understanding of the mechanisms triggered by Azadirachta indica.

Marine natural products targeting phospholipases A2

Phospholipases A(2) (PLA(2)s) form a family of enzymes catalyzing the hydrolysis of membrane phospholipids into arachidonic acid, which is the major precursor of pro-inflammatory eicosanoids. As a result, PLA(2)s have been considered as potential targets in anti-inflammatory drug discovery. Marine natural products are a rich source of bioactive compounds, including PLA(2) inhibitors. Here, we review the properties of marine PLA(2) inhibitors identified since the first discovery of PLA(2) inhibitory activity in the marine natural product manoalide in the mid 1980s.