Antitumor activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell death

Options for skin cancer treatment currently include surgery, radiotherapy, topical chemotherapy, cryosurgery, curettage, and electrodes-sication. Although effective, surgery is costly and unsuitable for certain patients. Radiotherapy can leave a poor cosmetic effect, and current chemotherapy is limited by low cure rates and extended treatment schedules. Here, we describe the preclinical activity of a novel topical chemotherapeutic agent for the treatment of skin cancer, 3-ingenyl angelate (PEP005), a hydrophobic diterpene ester isolated from the plant Euphorbia peplus. Three daily topical applications of 42 nmol (18 mug) of PEP005 cured a series of s.c. mouse tumors (B16 melanoma, LK2 UV-induced squamous cell carcinoma, and Lewis lung carcinoma; it = >14 tumors/group) and human tumors (DO4 melanoma, HeLa cervical carcinoma, and PC3 and DU145 prostate carcinoma; it = >4 tumors/group) previously established (5-10 mm(3)) on C57BL/6 or Fox1(nu) mice. The treatment produced a mild, short-term erythema and eschar formation but, ultimately, resulted in excellent skin cosmesis. The LD90 for PEP005 for a panel of tumor cell lines was 180-220 muM. Electron microscopy showed that treatment with PEP005 both ill vitro (230 tot) and ill vivo (42 nmol) rapidly caused swelling of mitochondria and cell death by primary necrosis. Cr-51 release, uptake of propidium iodide, and staining with the mitochondria dye JC1, revealed that PEP005 (230 muM) treatment of tumor cells ill vitro resulted in a rapid plasma membrane perturbation and loss of mitochondrial membrane potential. PEP005 thus emerges as a new topical anti-skin cancer agent that has a novel mode of action involving plasma membrane and mitochondrial disruption and primary necrosis, ultimately resulting in an excellent cosmetic outcome.

Ability of some plant extracts, traditionally used to treat ciguatera fish poisoning, to prevent the in vitro neurotoxicity produced by sodium channel activators

The effects of 31 plant extracts, which most are traditionally used to treat ciguatera fish poisoning in the Pacific area, were Studied on the cytotoxicity of mouse neuroblastoma cells produced by ouabain, veratridine and/or brevetoxin-3 or Pacific ciguatoxin-1. The cell viability was determined using a quantitative colorimetric method. A marked cytotoxicity of seven of the 31 plant extracts studied, was observed. Despite this, these plant extracts were suspected to contain active compound(s) against the cytotoxicity produced by brevetoxin (2 extracts), brevetoxin, ouabain and/or veratridine (3 extracts), or only against that of ouabain and/or veratridine (2 extracts). Among the 24 plant extracts that exhibited by themselves no cytotoxicity, 22 were active against the effect of brevetoxin or against that of both veratridine and brevetoxin. similar results were obtained when the seven most active plant extracts were reassayed using ciguatoxin instead of brevetoxin. In conclusion, the present work reports the first activity assessment of some plant extracts, achieved in vitro on a quite large scale. The fact that 27 plant extracts were found to exert, in vitro, a protective effect against the action of ciguatoxin and/or brevetoxin, paves the way for finding new active compounds to treat ciguatera fish poisoning, provided these compounds also reverse the effects of sodium channel activators. (c) 2005 Elsevier Ltd. All rights reserved.

Pollen distribution of sediment core MD96-2048 from the Western Indian Ocean

Glacial-interglacial fluctuations in the vegetation of South Africa might elucidate the climate system at the edge of the tropics between the Indian and Atlantic Oceans. However, vegetation records covering a full glacial cycle have only been published from the eastern South Atlantic. We present a pollen record of the marine core MD96-2048 retrieved by the Marion Dufresne from the Indian Ocean ~120 km south of the Limpopo River mouth. The sedimentation at the site is slow and continuous. The upper 6 m (spanning the past 342 Ka) have been analysed for pollen and spores at millennial resolution. The terrestrial pollen assemblages indicate that during interglacials, the vegetation of eastern South Africa and southern Mozambique largely consisted of evergreen and deciduous forests. During glacials open mountainous scrubland dominated. Montane forest with Podocarpus extended during humid periods was favoured by strong local insolation. Correlation with the sea surface temperature record of the same core indicates that the extension of mountainous scrubland primarily depends on sea surface temperatures of the Agulhas Current. Our record corroborates terrestrial evidence of the extension of open mountainous scrubland (including fynbos-like species of the high-altitude Grassland biome) for the last glacial as well as for other glacial periods of the past 300 Ka.

Pollen profile from Wurzacher Becken

Interglacial lacustrine sediments of 0.3-0.6 m thickness are found in the basin of Wurzach over a distance of about 9 km as detected by 5 borings. The interglacial bed is intercalated between lacustrine sediments of Würm (above) and glaciolacustrine sediments of the Younger Riss (below). Most of the Würmian sediments are silty-sandy, calcareous and varved deposits. They were deposited as bottom sediments of a delta, which had formed in the glacial lake filling the Wurzach basin during the Upper Würm. The terminal moraine of the Younger Riss is found in the N and S of the Reed of Wurzach. In the NE it is overlain by sediments of Würm and Holocene age. The pollen bearing part of the new profile represents the last interglacial period (except its earliest phases), the two Lower Würm interstadials, which are equivalents of the Brørup and Odderade interstadial phases, and a third interstadial, the Dürnten, known from other localities in the forelands of the Alps with a forest vegetation, which consisted mainly of spruce and larch trees, and the intercalated stadial phases. These interstadials are different from those described earlier by FILZER, which on the contrary represent cold periods with highly increased reworking of pollen. The equivalents of the Brørup, Odderade and Dürnten interstadials are the "Kiefer-Fichten-Kampfzeit" and part of the "Kiefernzeit mit Fichte" of FILZER. The characteristic series of climatic events known already from a great number of sites scattered all over Europe and again at Wurzach proves that the Riss/Würm- and the Eem interglacial periods are time-equivalents. Differing amounts of Carpinus and Abies at different places in the northern foreland of the Alps are related to the migration history of the two species during the last interglacial period and must not be used to distinguish different types of interglacials (type Zeifen, type Pfefferbichl).

Palaeoenvironment records of six sediment cores collected in the Gulf of Carpentaria

The Gulf of Carpentaria is an epicontinental sea (maximum depth 70 m) between Australia and New Guinea, bordered to the east by Torres Strait (currently 12 m deep) and to the west by the Arafura Sill (53 m below present sea level). Throughout the Quaternary, during times of low sea-level, the Gulf was separated from the open waters of the Indian and Pacific Oceans, forming Lake Carpentaria, an isolation basin, perched above contemporaneous sea-level with outlet channels to the Arafura Sea. A preliminary interpretation is presented of the palaeoenvironments recorded in six sediment cores collected by the IMAGES program in the Gulf of Carpentaria. The longest core (approx. 15 m) spans the past 130 ka and includes a record of sea-level/lake-level changes, with particular complexity between 80 and 40 ka when sea-level repeatedly breached and withdrew from Gulf/Lake Carpentaria. Evidence from biotic remains (foraminifers, ostracods, pollen), sedimentology and geochemistry clearly identifies a final marine transgression at about 9.7 ka (radiocarbon years). Before this transgression, Lake Carpentaria was surrounded by grassland, was near full, and may have had a surface area approaching 600 km-300 km and a depth of about 15 m. The earlier rise in sea-level which accompanied the Marine Isotopic Stage 6/5 transgression at about 130 ka is constrained by sedimentological and biotic evidence and dated by optical- and thermoluminescence and amino acid racemisation methods.

Pollen from multicores surface samples from Namaquan mudbelt

The distribution of pollen in marine surface sediments offshore of the west coast of South Africa has been investigated to aid in the interpretation of marine pollen records of onshore vegetation changes. A transect of sediment surface pollen samples retrieved from the Namaqualand mudbelt from just south of the Orange River mouth (29°S) to St Helena Bay (33°S) indicates distinctive pollen spectra reflecting vegetation communities on the adjacent continent. Pollen concentration increases southwards, partly in relation to greater pollen productivity due to higher biomass and density of fynbos vegetation and of sedimentary processes and low pollen concentrations consequent to dilution with silt and clay from the Orange River. The distribution of specific pollen taxa suggests that the Orange River is a major contributor of pollen to the northern mudbelt declining southwards, while the pollen distribution in the central mudbelt is largely attributable to seasonal inputs of pollen from offshore berg winds and local ephemeral Namaqualand rivers. The typical fynbos elements dominate in the southern mudbelt indicating a pollen source mainly in the fynbos vegetation types. These conclusions support a companion analysis of fossil pollen records of two marine sediment cores from the northern and southern mudbelt respectively. This study demonstrates that pollen records from marine sediment cores in the Namaqualand mudbelt have the potential to be a tool to reconstruct palaeovegetation on the adjacent continent. However, to better reconstruct the palaeoclimate of South Africa and fully understand the relations between terrestrial and marine deposits, more marine surface sediments along the western coast of South Africa as well as more terrestrial surface sediments need to be studied.