Skin cancer is a growing problem in Australia and world wide. Skin cancer is most often associated with over exposure to the sun and resulting sundamge to the skin's cells, causing changes in DNA of the skin cells. The following article is a report on a plant, Milkweed (Euphorbia peplus), which research shows has anti-cancer properties.
Herbal Cure for Skin Cancer?
Growing Milkweed a plant with prospective anti-cancer properties
A review of the medicinal potential of members of the Euphorbiaceae family.
A report for the Rural Industries Research and Development Corporation by Dr Craig Davis and Dr Peter Parsons January 2002
Growing Milkweed, a plant with prospective anti-cancer properties: A review of the medicinal potential of members of the Euphorbiaceae family.
The economy of Australia since settlement has depended heavily on primary production. Continuing innovation in the development of products and technology has been required to cope with changing world markets and conditions. At the personal level, the harsh Australian environment has taken a toll on the health of rural stakeholders, as well as on the Australian population at large. This can be seen in the high incidence of skin cancer, particularly in outdoor workers.
The present project may result in a unique opportunity for primary producers to contribute to their own wellbeing through the development of an effective treatment for non-melanoma skin cancer. A new, specialist crop might also emerge.
Compounds from a common but tractable weed are being developed for this purpose by a Brisbane-based, Australian-owned biotechnology company, Peplin Biotech Pty Ltd. Complementary expertise is being contributed by the Queensland Department of Primary Industries and by the Queensland Institute of Medical Research, one of the biggest medical research institutes in Australia.
The aim is to evaluate methods for the complete mechanisation of milkweed cultivation. This will include methods of seed production. The requirements for large-scale agriculture will be ascertained, using the expertise and equipment pooled from the wide variety of specialists in the Queensland Department of Primary Industries. Economical agricultural production is a major requirement for progressing the skin cancer treatment.
Peplin Biotech has discovered a novel class of natural compounds, purified from Euphorbia, which show great potential in the laboratory as a potent treatment for a wide range of human cancers including breast and prostate cancer, leukaemia, melanoma and other skin cancers, as well as lung, colorectal and cervical cancer.
An early clinical trial on thick and thin non-melanoma skin cancers has confirmed that the compounds are very effective in producing long-term (possibly permanent) responses in human patients without any evident systemic toxicity when applied topically. This is highly significant because current topical methods of drug treatment require long periods of application without being fully effective, and physical methods (e.g. surgery) are expensive and difficult to apply to the large areas affected, especially in older people.
Topical treatment of non-melanoma skin cancer - basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) - will be the first medical application of the E.peplus product. These are the most common human cancers, and most Australians will develop one or more BCC or SCC in their lifetimes. Mortality from melanoma is about 50% in the state of Queensland and morbidity is high.
The treatment of non-melanoma skin cancer costs over $200 million dollars in Australia, making it the most expensive cancer. The rate of increase in skin cancer has slowed, presumably due to education in prevention measures but the incidence continues to be high and may increase with the ageing of the population. Western countries with less UV flux than Australia also have high incidences of non-melanoma skin cancer, due to sun-seeking lifestyles. In the US, the annual cost of non-melanoma skin cancer has been estimated at US$3.5 billion. There is therefore a need for a simple, reliable method of treating skin cancer on a large scale.
Over 70% of current pharmaceuticals are natural products or have been developed from a natural product lead. E.peplus is one of a number of plants in the Euphorbiaceae family that has attracted attention as a home remedy for skin cancer because of its milky sap. However, a survey by Peplin Biotech of over 200 species of the Euphorbiaceae family has shown that only E.peplus has the desired attributes of anti-cancer efficacy in vitro and in vivo. In addition, E.peplus is not a noxious weed, it grows rapidly, produces harvestable seed and it is potentially suitable for large-scale agricultural production. Thought to originate from Europe, E.peplus is now widespread throughout the world and can be found in most gardens.
Methods have been developed by Peplin Biotech for the extraction and purification of compounds from E.peplus in the laboratory, and these are currently being scaled-up for commercial production.
It is anticipated that the overall cost of producing the active ingredient in pure form will result in a commercially viable treatment, provided the cost of agricultural production can be kept low. The limiting factor in capturing commercial value from these discoveries is therefore the availability of plant feedstock for extraction of the active compounds. Developing large-scale agricultural production can solve this problem. Currently, the plant is sown by hand and tended in plots of 10-100 sq m. Harvesting of seed and plant is also carried out by hand. Sufficient information has now been obtained to show that there is no inherent difficulty in large-scale production in a variety of locations and environments in Australia.
We plan to evaluate methods for complete mechanisation of E.peplus cultivation and sap production. This will include methods of seed production, since the current supply of seed will need to be greatly expanded. The requirements for large-scale agriculture will be ascertained, using the expertise and equipment pooled from the wide variety of specialists in the DPI. The next critical step is to develop methods suitable for broad-acre, mechanised production.
Background on members of the Euphorbiaceae family
The Euphorbiaceae family covers a wide variety of plants (>2000 world-wide) including weeds, trees and other types of plants of the Euphorbia species, many of which are slow-growing succulents (http://florawww.eeb.uconn.edu/acc_num/198500271.html). When the stems are cut, many members exude a milky sap (latex) which has an unpleasant taste and is toxic when ingested in significant quantities. Such chemical properties, combined with the presence of thorns on some species (e.g. Crown of Thorns), presumably protect the plant from grazing in the arid regions of the world where many of the family originate.
A variety of inconclusive reports on the therapeutic potential effects of the sap of these plants have been published along with reports of tumour promotion and skin and ocular irritation. The most intensively studied species of this group is Euphorbia pilulifera L (synonyms E.hirta L., E.capitata Lam.), whose common names include pill-bearing spurge, snakeweed, cat’s hair, Queensland asthma weed and flowery-headed spurge. The plant is widely distributed in tropical countries, including India, and in Northern Australia (including Queensland).
A recent report describes selective cytotoxicity of a number of tiglilane diterpene esters from the latex of Euphorbia poisonii, a highly toxic plant found in Northern Nigeria, which is used as a garden pesticide. One of these compounds has been reported to have a selective cytotoxicity for the human kidney carcinoma cell line A-498 more than 10,000 times greater than that of Adriamycin (Fatope et al., 1996).
Euphorbia hirta plants and extracts thereof have been considered for a variety of purposes, including tumor therapy (European Patent Application No. 0 330 094), AIDS-related complex and AIDS (Hungarian Patent Application No. 208790) and immune stimulation and anti-fungal treatment of open wounds (German Patent Application No. 4102054).
There are isolated reports of anti-cancer activity of various Euphorbia preparations (see Fatope et al., 1996; Oksuz et al., 1996; http://www.floridaplants.com/Med/cancer.htm). On the other hand, compounds present in at least one Euphorbia species were reported to be carcinogenic (Evans and Osman, 1974; Stavric and Stoltz, 1976; Hecker, 1971), one species has a skin-irritant and tumour-promoting effect (Gundidza and Kufa, 1993) and another species reduces EBV-specific cellular immunity in patients with Burkitt’s lymphoma (Imai, 1994).
Given the above diversity of bioactivity amongst members of the Euphorbiaceae family, it is notable that Peplin Biotech has identified compounds from E.peplus (of the Euphorbiaceae family) which are effective for the treatment of skin cancer in humans.
Community use of Euphorbia peplus
Euphorbia peplus, commonly known in Australia as the radium weed or milkweed, is a non-invasive weed, most probably introduced to Australia by European settlers in the early 1800s for its medicinal value (Maiden, 1917; Pearn, 1987). Early Australian folklore suggested that the irritant sap had application against warts, corns, waxy growths, sun cancer and rodent ulcers (Maiden 1917; Hartwell, 1969). In Europe, folklore included the treatment of asthma and catarrh (Rizk et al., 1985; http://www.homeoint.org/clarke/e/euphorb_peplus.htm), and as a purgative. E.peplus was widely used in the Ukraine around the turn of the century as a treatment for cancer of the stomach, liver and uterus (Shimansk'ka, 1961). A letter to the Medical Journal of Australia reported a case of self-treatment using E.peplus sap to remove a basal cell carcinoma from the chest by a local farmer
(Weedon and Chick, 1976). More recently, a survey of home remedies for skin cancer and solar keratoses used by residents of the Nambour district of Queensland concluded that E.peplus was unanimously considered an effective treatment (Green and Beardmore, 1988).
Development of anti-cancer compounds from Euphorbias by Peplin Biotech Pty Ltd
Peplin Biotech Limited is a Brisbane-based Life Sciences Company which is listed on the Australian Stock Exchange. Its present sole activity is research and development to support the commercialisation of a novel group of compounds discovered in 1997 by its founder, Dr James Aylward, a former CSIRO biochemist. It conducts all of its research by way of external contracts
with research organisations such as the Queensland Department of Primary Industries, the Queensland Institute for Medical Research, the CSIRO, as well as at various universities and hospitals. A more complete description of the Company and its undertakings can be found at http://www.peplin.com.
The Queensland Department of Primary Industries (DPI) is currently playing a key role in optimising the conditions for agriculture of E.peplus, a plant which, although ubiquitous as a weed in gardens and nurseries, has never before been cultivated. Covering possibly the widest range of climates in Australia, the DPI has a broad range of expertise in all aspects of agriculture, including the development of exotic crops. Current small-scale experimental work with E.peplus involves the DPI’s Centre for Food Technology and Queensland Horticulture Institute establishment at Redlands, near Brisbane.
The Queensland Institute for Medical Research (QIMR) is one of the largest biomedical research institutes in Australia, with a staff of approximately 400. A significant proportion of its effort is devoted to cancer research, and expansion into a new Comprehensive Cancer Centre is currently underway. The ontribution of QIMR in the present context is to assay the compounds produced by E.peplus under various conditions of agriculture, using chemical and bioactivity measurements.
The means are available to conduct clinical trials with a purified compound, delivered in a suitable cream. Problems of extraction of compound and purification have been largely overcome. The rate-limiting step at present is shortage of compound, due to lack of knowledge about large-scale agriculture.
We plan to evaluate methods for complete mechanisation of E.peplus cultivation and sap production.
The requirements for large-scale agriculture will be ascertained, using the expertise and equipment pooled from the wide variety of specialists in the DPI. The next critical step is to develop methods suitable for broad-acre, mechanised production.
A clinical trial with E.peplus latex in Brisbane
With the above background, Peplin Biotech began a study to determine the performance of crude sap against a variety of cancers, with an emphasis on skin cancers. Surprisingly, the sap was not only efficacious against a variety of skin cancer cell lines, including strains of malignant melanoma resistant to conventional chemotherapeutic agents, but also had powerful cell inhibitory activity against a wide range of other tumours tested, including breast cancer cells.
12 weeks after 3 daily treatments
This promising in vitro data, coupled with the extensive community use for the topical treatment of skin cancer without any reported side effects, resulted in ethics approval being granted for a Phase I/II clinical trial of the crude sap on skin cancer patients at the Mater Hospital in Brisbane. The trial was restricted to patients who had failed or refused conventional therapy. The skin cancers
treated in the trial, therefore, tended to be at an advanced stage and some were on sites where healing after surgery or radiotherapy was a serious problem (e.g. the lower leg in older patients). Long-term complete remissions were confirmed by biopsy and were >80%.
Active compounds from E.peplus:
Structure and bioactivity assays
One of the first observations made in current research on E.peplus sap was that it was selectively toxic to tumour cells compared with normal cells in culture. Moreover, at concentrations of the sap too low to effect direct cell killing, surviving tumour cells examined by light microscopy demonstrated an altered morphology (i.e. a dendritic appearance). In the case of melanoma, the morphological changes were characteristic of normal melanocytes. Further cell observations led to the conclusion that the diluted sap was acting as a potent differentiation control agent.
Bioactivity guided fractionation has led to the identification of the active principles responsible for the selective cytotoxicity and differentiation control activity. The activity resided in macrocyclic diterpenes of three families, namely ingenane, pepluane and jatrophane. Pepluane and jatrophane are novel molecules with unusual conformations. First documented in the literature in 1998 by Jakupovic et al., they are reported to be non-inflammatory. Ingenane, on the other hand is responsible for the irritant properties of the latex (Jakupovic et al., 1998). HPTLC chromatographic techniques were developed at QIMR to enable the separation and concentration of sufficient quantities of each of these components to undertake further in vitro and in vivo studies. The specific molecules in question are: 20-acetyl-ingenol-3-angelate (ingenane) and other ingenol esters - 5,8,9,10,14- pentaacetoxy-3-benzoyloxy-15-hydroxypepluane (pepluane), 15-pentaacetoxy-9-nicotinoyloxy-14- oxojatropha-6 (1),11E-diene (jatrophane 1), 2,5,7,9,14-hexaacetoxy-3-benzoyloxy-15-hydroxy- jatropha-6(17),11E-diene (jatrophane 2), 2,5,14-triacetoxy-3-benzoyloxy-8,15-dihydroxy-7- isobutyroyloxy-9-nicotinoyloxyjatropha-6(17),11E-diene (jatrophane 3), 2,5,9,14-tetraacetoxy-3- benzoyloxy-8,15-dihydroxy-7-isobutyroyloxyjatropha-6(17),11E-diene) jatrophane 4), 2,5,7,14- tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxyjatropha-6(17),11E-diene (jatrophane 5) and 2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17),11E-diene (jatrophane 6).
Mouse studies using in vivo models for skin cancer have been encouraging, with cures obtained when crude sap or purified diterpenes from E.peplus were used topically on human malignant melanoma xenografts in nude mice and B16 mouse melanoma in C57 black mice.
Intellectual property surrounding the use of ingenane, jatrophanes and pepluane as anti-neoplastic differentiation control agents are the subject of patent application No. PCT/AU98/00656 and are the property of Peplin Biotech Pty Ltd.
Novel mechanism of anti-cancer action
Key results have been obtained from a range of tumour and normal cells (primarily the human melanoma cell line MM96L), indicating that a particular enzyme (a kinase) is the primary target for the E.peplus-derived compounds. This results in a signal cascade inside the cell which affects growth, survival, differentiation and release of chemokines which communicate to other cells and tissues. The overall outcome for cancer control probably results from a combination of many of these changes.
As part of ongoing drug development by Peplin Biotech, a range of assays have been established to compare the bioactivities of crude extracts from plants as well as pure compounds. We are, therefore, in a strong position to rapidly evaluate any changes in bioactivity.
Screening of other members of the family for bioactivity
The Euphorbiaceae plant family consists of over 2000 members but only a few species are worth considering as commercial sources of compounds. This is based on our recent survey of >200 species made available through the Succulent Society of Queensland and the Queensland Herbarium. Most of
these had significant in vitro activity but were succulents, which grow very slowly. Two other candidate species that have been cultivated (Synadenium grantii and E.tirucalli) are readily propagated and produce copious amounts of sap with high in vitro activity but their active diterpenes have been reported to be phorbol derivatives which may be less attractive for commercial development than the E.peplus-derivedcompounds. Several other weeds from the Euphorbiaceaefamily have been considered (see below).
Is E.peplus the most suitable species for production of anti-cancer compounds?
Euphorbia peplus grows wild in temperate climates around the world (http://www.nhm.ac.uk/science/projects/fff/ChekLisE.htm). While a number of other related species with milky saps (http://www.wa.gov/agr/weedboard/weed_info/leafyspurge2.html) have been considered, these have a range of drawbacks. E.terracina, E.lathryis and E.davidii grow in Australia as weeds but are listed as noxious weeds in various States and are therefore unacceptable for agriculture. In addition, our testing of E.terracina sap revealed insufficient bioactivity in culture but to cure tumours in the mouse model. E.paralias is a woody plant that grows on beach sand dunes along the southeastern coast of Australia. It is considered to be a noxious weed, both here and in Europe. The bioactivity of its sap is not high, the cultivatable areas are very limited and the plant grows slowly. E.esula is a seriously noxious weed in the USA and is not found in Australia. The Euphorbia succulents grow extremely slowly and would not produce enough biomass to be economically feasible sources of the desired compounds.
We have propagated some 1000 plants of the shrub Synadenium grantii but its sap has poor activity in the mouse model and contains a phorbol ester rather than the preferred ingenane esters. Similar results have been obtained with sap from the shrub E.tirucalli (naked lady).
E.peplus, therefore, remains our species of choice because of its ease of cultivation, history of safe community use and demonstrated efficacy in a clinical trial of the crude sap and in animal models using the purified compounds.
Agriculture of E.peplus
The large number of asymmetric centres in these molecules makes synthesis unattractive on a commercial scale. Attention has therefore been given to developing the plant source (see Appendix II for details of a student project). This work is currently progressing through agronomic trials undertaken with the Queensland Department of Primary Industries.
E.peplus grows readily from seed in temperate and subtropical climates, maturing in 12-14 weeks. We have grown it all the year round at appropriate locations in Australia. Potential viral problems have been discussed (http://image.fs.uidaho.edu/vide/famly058.htm). Rust may be a problem in the maturing stages. The seeds are small (1700/gram) but have >70% germination rate. Although found as a weed in many gardens and nurseries, E.peplus never spreads spontaneously beyond the limits of shade and is not listed as a noxious weed in any Australian State. It is easy to weed by hand, and is killed readily by weedicides including Roundup. It is therefore unlikely to become a serious competitor with other crops.
A process has been developed for the laboratory extraction and purification of compounds from green or dried plant material. Quality control of batches can be done quickly and inexpensively by in vitro bioassay and mass spectroscopy. Yield of plant is currently 1-1.5 kg/sq meter, and yield of compounds is approximately 100-300 mg/kg wet weight of plant.
With the assistance of the Queensland Department of Primary Industry, we plan to evaluate methods for complete mechanisation of E.peplus cultivation and sap production. It should be straightforward to determine the requirements for large-scale agriculture, given the expertise and equipment pooled from the wide variety of specialists in the DPI. The next critical step is to develop methods suitable for broad-acre, mechanised production.
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Dr Craig Davis
Dr Peter G. Parsons
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Published in January 2002
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Natural Skin Care Newsletter
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All our skin care products have been developed primarily to help our patients with a wide range of skin care problems for the past 30 years.
Susan and Danny practice Western herbal medicine, Acupuncture, Chinese herbal medicine, Remedial body therapies at their private practice in the lower Blue Mountains, West of Sydney.
Their combined experience in treating skin and other disorders is well over 50 years and they're happy to help you regain your optimal health.
- - -Topical Articles on skin care and the benefits of using NATURAL skin care products
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Need Help with a Skin Problem?
Consult The Virtual Skin Doctor
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Age Defying Natural Skin Care Systems for even the most sensitive skin types.
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Why you should choose Wildcrafted's range of Natural & Organic Skin Care Products.
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Look Younger & Feel Younger with Wildcrafted's Age-Defying Essence
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WILDCRAFTED HERBAL PRODUCTS™
ABN 97 131 307 643
Wildcrafted's Natural Skin Care Products are Your Natural Skin Care Solution
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