Combretum caffrum (PROTA)

Plant Resources of Tropical Africa Introduction

List of species

General importance
Geographic coverage Africa
Geographic coverage World
Medicinal
Timber
Fuel
Ornamental
Auxiliary plant

Combretum caffrum (Eckl. & Zeyh.) Kuntze

Protologue: Revis. gen. pl. 3(3): 87 (1898).

Family: Combretaceae

Synonyms

• Combretum salicifolium E.Mey. ex Hook. (1843).

Vernacular names

• Cape bush-willow, bush-willow tree, African bush-willow, African willow tree (En).

Origin and geographic distribution

Combretum caffrum is endemic to the Eastern Cape and KwaZulu-Natal in South Africa. It is traded as a rare ornamental in South Africa, Australia and the United States.

Uses

The Xhosa people of the Eastern Cape use the bark of Combretum caffrum in combination with a number of other herbs as an anti-cancer treatment. The bark is widely used as a general tonic. A root decoction is added to bath water to treat general body pain. The Zulu people use the plant extract as a spear poison. They also use the root bark as a charm against enemies. Leaf juice is used as eye drops to treat conjunctivitis in domestic animals. A stem bark decoction is given to cattle with redwater disease. Honey of Combretum caffrum is very bitter, but no problems have been recorded from human consumption. The timber is yellow and dense, and is used for poles and fuel wood. It is not very durable. The tree is left in the field as a shade tree.

Production and international trade

The bark, leaves and roots of Combretum caffrum are commonly sold on local markets throughout South Africa. In South Africa a formulation made from a bark decoction is produced commercially and sold as an anti-cancer remedy. Combretum caffrum bark can be purchased on the internet at US$ 22 per 100 g.

Properties

A range of stilbenoids, combretastatins A1–A4, B1–B4, D1 and D2, were isolated from the leaves, fruits and stem bark. From the stem bark also several phenanthrenes, including three 9,10-dihydrophenanthrenes and di-phenathreben B, have been isolated. Other major, but non-active, constituents isolated were 3,3’,4’-tri-O-methylellagic acid and acacetin.

A huge number of publications appeared since combretastatins were found to be highly active in inhibiting the growth of P-388 and L1210 leukemia cell lines. Especially combretastatin A4 was found to be active against murine melanoma, a variety of other human solid tumours and a series of malignant human B-lymphoid cell lines. Many of the combretastatins, especially combretastatin A1, A4 and B1, are also tubulin-binding agents, and so have unique antitubulin and antivascular properties. They are structurally related to colchicine, which induces vascular-mediated tumour necrosis in animal models. Several synthetic analogues are also now available, including the Aventis Pharma compound AVE8062. More soluble, phosphated forms of A1 (A1P) and especially A4 (A4P) are commonly used for in vitro and in vivo studies. These are cleaved to the natural forms by endogenous phosphatases and are taken up into cells. In animal models, A4P caused a prolonged and extensive shutdown of blood flow in established tumour blood vessels, with much less effect in normal tissues. The lead compound, A4P, is currently in Phase I clinical trial as a tumour vascular targeting agent, and a maximum tolerated dose in the range 60–68 mg/m² has been established. Based on the Phase I data, combination studies of A-4P with established therapies are in progress.

A structure-activity relationship study of combretastatin A4 led to the discovery of a potent cancer cell growth inhibitor designated phenstatin. A benzophenone derivative of combretastatin A4, designated hydroxyphenstatin, showed remarkable antineoplastic activity. While hydroxyphenstatin was a potent inhibitor of tubulin polymerization with activity comparable to that of combretastatin A1, the phosphorylated derivative was inactive.

Di-phenathreben B showed highly significant antitumour activity when tested on the murine P-388 lymphocytic leukaemia cell line.

Acetone, methanol and aqueous extracts and a water decoction of the stem bark showed in vitro antifungal and antibacterial activity against Gram-positive bacteria. Both acetone and methanolic stem bark extracts showed highly significant antifungal activity against Alternaria alternaria, Mucor hiemalis and Schizophyllum commune. Methanolic extracts also showed significant activity against Aspergillus niger and Penicillium notatum. The hot water decoction prepared in the traditional way was found to be more active than the cold water extract.

Combretastatin B5 showed significant antibacterial and antifungal activity. Combretastatin A4, A5, and A6 were also found to inhibit growth of Neisseria gonorrhoeae.

Description

Deciduous, small to medium-sized spreading tree up to 10 m tall; young branches densely short-hairy, pinkish after shedding the bark. Leaves subopposite or sometimes in whorls of 3, simple and entire; stipules absent; petiole 1–5(–8) mm long, densely short-hairy; blade narrowly elliptical, up to 4–10 cm × 1–2.5 cm, apex acute, mucronate, base cuneate, lateral nerves prominent, in 6–8(–12) pairs, both sides almost glabrous or densely short-hairy beneath, shiny green above. Inflorescence an axillary almost spherical spike up to 2(–3) cm long, rarely forming short panicles by the suppression of leaves on short shoots. Flowers bisexual, regular, 4-merous, cream or yellow, usually congested; receptacle consisting of 2 parts, lower part 1.5–2.5 mm long, usually densely short-hairy; upper part broadly campanulate, 2–2.5 mm long, short-hairy; sepals ovate, c. 1 mm long; petals obovate, narrowly obovate, spoon-shaped or narrowly elliptical, c. 1.5 mm × 1 mm, apex sometimes notched, glabrous; stamens 8, filaments c. 5 mm long; ovary inferior, 1-celled. Fruit a 4-winged nut, almost round to broadly elliptical, 1.3–1.8 cm long, reddish brown, short-hairy and scaly, stipe up to 7 mm long, wings c. 5 mm broad, indehiscent, 1-seeded. Seedling with hypogeal germination.

Other botanical information

Combretum is a very large genus, comprising about 250 species and distributed worldwide in the tropics and subtropics. About 140 species occur in tropical Africa; c. 20 species are endemic to Madagascar.

Combretum caffrum is very similar to Combretum erythrophyllum (Burch.) Sond., ‘river bush willow’, which occurs through most of eastern South Africa, Swaziland, Zimbabwe and Mozambique, and which prefers a similar habitat.

Growth and development

Combretum caffrum flowers from late August to early November, but has also been observed in March. It fruits from January to May. A huge number of fruits is produced and gives the tree a reddish-brown appearance. Combretum caffrum sheds its leaves in early spring, just before new leaves arrive.

Ecology

Combretum caffrum occurs mainly along river and stream banks, in sand soil or alluvium, occasionally on hill and mountain slopes, in evergreen or coastal forest, from sea-level up to 1100 m altitude, with at least 500 mm of annual rainfall. Combretum caffrum can also grow on degraded sandy, gravelly and even saline soil with good drainage. It tolerates rather dry conditions, but does not tolerate frost and waterlogging. Branch tips are damaged at temperatures below 5°C.

Propagation and planting

For best germination seeds should be extracted from the hard fruit. The seeds should be soaked for a few hours in water and treated with a fungicide before being sown in a sandy soil. They germinate after 7 days when kept at a constant temperature of 30°C. If sown in a greenhouse with soil heating at night, 60% of the seeds germinate after 8 to 25 days. If sown in an outdoor seedbed, 40% of the seeds germinate after15 to 40 days. Under optimal conditions, seedlings can grow c. 60 cm during the first year. Seedlings require 4–6 months in a nursery before planting out. The seeds retain their viability for several months if kept dry and free from insects at a maximum temperature of 20°C, and for at least 2 years when dried below 8% humidity. Natural regeneration is hampered by bush fires and frequent dry spells.

Management

Combretum caffrum can be pollarded, coppiced, trimmed and pruned. For fast growth fertilizer should be applied regularly on Combretum caffrum seedlings. When grown in a container as an ornamental plant, Combretum caffrum requires frequent repotting to control its size. It grows well both in shade and bright sunlight; it is vulnerable though to cold wind and frost, especially young plants which should be protected during the first two years. During cool weather, Combretum caffrum is prone to root rot and then requires drier soil.

Diseases and pests

The seeds of Combretum caffrum are often parasitized.

Harvesting

The leaves, stem bark and root bark of Combretum caffrum are harvested from the wild or from home gardens for local use, whenever the need arises. Removal of the stem bark should be done in small pieces and not by ring barking, as is commonly done.

Handling after harvest

The harvested bark, leaves and roots are washed and air-dried before use or trade. They can also be dried in the sun and stored in airtight containers for later use. A decoction of the leaves, root bark or stem bark can be stored in bottles to be used within a week. If refrigerated, it can be stored for much longer.

Genetic resources

Combretum caffrum is widespread in most of its area of distribution and is not in danger of genetic erosion. However, excessive harvesting of Combretum caffrum for medicinal use calls for measures to protect some of the natural stands. No systematic germplasm collection or preservation programme exist. However, in South Africa there are small collections in botanical gardens, private gardens and research institutions.

Prospects

In view of the demonstrated anticancer properties of combretastatins from Combretum caffrum, further clinical research will prove worthwhile to enhance their potential for anticancer treatment. Research on propagation and domestication as well as quality control and measures for sustainable utilization are needed.

The bushy nature, attractive foliage and fruits of Combretum caffrum makes it a suitable ornamental plant and interest in this regard is growing.

Major references

• Afolayan, A.J., Grierson, D.S., Kambizi, L., Madamombe, I. & Masika, P.J., 2002. In vitro antifungal activity of some South African medicinal plants. South African Journal of Botany 68: 72–76.

• Bilenker, J.H., Flaherty, K.T., Rosen, M., Davis, L., Gallagher, M., Stevenson, J.P., Sun, W., Vaughn, D., Giantonio, B., Zimmer, R., Schnall, M. & O’dwyer, P.J., 2005. Phase 1 trial of combretastatin A-4 phosphate with carboplatin. Clinical Cancer Research 15: 1527–1533.

• Coates Palgrave, K., 2002. Trees of southern Africa. 3rd Edition. Struik Publishers, Cape Town, South Africa. 1212 pp.

• Eloff, J.N., Katerere, D.R. & McGaw, L.J., 2008. The biological activity and chemistry of the southern African Combretaceae. Journal of Ethnopharmacology 119: 686–699.

• Hsieh, H.P., Liou, J.P. & Mahindroo, N., 2005. Pharmaceutical design of antimitotic agents based on combretastatins. Current Pharmaceutical Design 11(13): 1655–1677.

• Kanthou, C., Greco, O., Stratford, A., Cook, I., Knight, R., Benzakour, O. & Tozer, G., 2004. The tubulin binding agent combretastatin A-4-phosphate arrests endothelial cells in mitosis and induces mitotic cell death. American Journal of Pathology 165(4): 1401–1411.

• Kingston, D.G.I., 2009. Tubulin-interactive natural products as anticancer agents. Journal of Natural Products 72(3): 507–515.

• Pettit, G.R., Singh, S.B., Niven, M.L. & Schmidt, J.M., 1988. Cell growth inhibitory dihydrophenanthrene and phenanthrene constituents of the African tree Combretum caffrum. Canadian Journal of Chemistry 66(3): 406–413.

• Vitale, I., Antoccia, A., Cenciarelli, C., Crateri, P., Meschini, S., Arancia, G., Pisano, C. & Tanzarella, C., 2007. Combretastatin CA-4 and combretastatin derivative induce mitotic catastrophe dependent on spindle checkpoint and caspase-3 activation in non-small cell lung cancer cells. Apoptosis 12(1): 155–166.

• Young, S.L. & Chaplin, D.J., 2004. Combretastatin A4 phosphate: background and current clinical status. Expert Opinion on Investigational Drugs 13(9): 1171–1182.

Other references

• Bhat, R.B. & Jacobs, T.V., 1995. Traditional herbal medicine in Transkei. Journal of Ethnopharmacology 48: 7–12.

• Beauregard, D.A., Thelwall, P.E. & Chaplin, D.E., 1998. Magnetic resonance imaging and spectroscopy of combretastatin A-4 prodrug-induced disruption of tumour perfusion and energetic status. British Journal of Cancer 77: 1761–1767.

• Cunningham, A.B., 1990. People and medicines: the exploitation and conservation of traditional Zulu medicinal plants. In: Ihlenfeldt, H.-D. (Editor). Proceedings of the twelfth plenary meeting of AETFAT, 4–10 September 1988, Hamburg, Germany. Mitteilungen aus dem Institut für Allgemeine Botanik Hamburg 23b: 979–990.

• Eloff, J.N., 1999. The antibacterial activity of 27 southern African members of the Combretaceae. South African Journal of Science 95: 148–152.

• Galbraith, S.M., Chaplain, D.J. & Lee, F., 2001. Effects of combretastatin A4 phosphate on endothelial cell morphology in vitro and relationship to tumour vascular targeting activity in vivo. Anticancer Research 21: 93–102.

• Grosios, K., Holwell, S.E. & McGown, A.T., 1999. In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug. British Journal of Cancer 81: 1318–1327.

• Holwell, S.E., Cooper, P., Grosios, K., Lippert, J.W., Pettit, G.R., Shnyder, S.D. & Bibby, M.C., 2002. Combretastatin A-1 phosphate, a novel tubulin-binding agent with in vivo anti vascular effects in experimental tumours. Anticancer Research 22(2a): 707–712.

• Hutchings, A., Haxton Scott, A., Lewis, G. & Cunningham, A., 1996. Zulu medicinal plants: an inventory. University of Natal Press, Pietermaritzburg, South Africa. 450 pp.

• Iyer, S., Chaplain, D., Rosenthal, D., Boulares, A., Li, L.-Y. & Smulson, M., 1998. Induction of apoptosis in proliferating human endothelial cells by the tumour-specific antiangiogenesis agent combretastatin A-4. Cancer Research 58: 4510–4514.

• Katerere, D.R.P., 2001. Phytochemical and pharmacological studies of African Combretaceae. PhD Thesis. University of Strathclyde, Glasgow, United Kingdom.

• Masika, P.J. & Afolayan, A.J., 2002. Antimicrobial activity of some plants used for treatment of livestock disease in the Eastern Cape, South Africa. Journal of Ethnopharmacology 83: 129–134.

• Nam, N.H., 2003. Combretastatin A-4 analogues as antimitotic antitumor agents. Current Medicinal Chemistry 10(17): 1697–722.

• Pettit, G.R, Singh, S.B. & Schmidt, J.M., 1988. Isolation, structure, synthesis, and antimitotic properties of combretastatins B-3 and B-4 from Combretum caffrum. Journal of Natural Products 51(3): 517–527.

• Tozer, G.M., Kanthou, C., Parkins, C.S. & Hill, S., 2002. The biology of the combretastatins as tumour vascular targeting agents. International Journal of Experimental Pathology 83(1): 21–38.

Author(s)

• A. Maroyi, Department of Biodiversity, School of Molecular and Life Sciences, University of Limpopo, Private Bag X 1106, Sovenga 0727, South Africa

Correct citation of this article

Maroyi, A., 2011. Combretum caffrum (Eckl. & Zeyh.) Kuntze. In: Schmelzer, G.H. & Gurib-Fakim, A. (Editors). PROTA (Plant Resources of Tropical Africa / Ressources végétales de l’Afrique tropicale), Wageningen, Netherlands. Accessed 6 March 2025.

• See the Prota4U database.