A Hidden Treasure: The Borneo Mistletoes.

The European mistletoe, Viscum album, is the most common consumed adjuvant among cancer patients in Europe. Its success warrants a report on three most apparent mistletoes found in Borneo Island, namely Scurrula ferruginea, Macrosolen cochinchinensis, and Dendrophthoe curvata. The traditional and pharmacological uses of these mistletoes include antibacterial, anticancer, antiviral, antihypertensive, antioxidative, and cytotoxic effects. Phytochemicals such as flavonols, alkaloids, tannins, and gallic acid have been reported in one of these mistletoes. This review discusses the potential of these mistletoes as therapeutic agents.

INTRODUCTION

Mistletoes are often associated with Christmas decorations in cold climate regions. The success of European mistletoe, Viscum album, as a source of anticancer drug has prompted us to look into the tropical mistletoes. There is not only a dearth of knowledge regarding tropical mistletoes but also a lack of awareness even among the local people in the region. Mistletoes are obligate parasitic plants which grow on stems of trees with the aid of a sophisticated structure called haustorium. Mistletoes may encounter varying responses from host plants for their haustorial penetration.[1] Taxonomically, mistletoes are from the order of Santalales and are found in three families: Santalaceae (inclusive of the Viscaceae), Loranthaceae, and the Misodendraceae.[2] The species under the various genera are mentioned in Table 1.

Table 1

The three families of mistletoes within the order of Santalales

The most common mistletoe known as V. Album (English name: mistle), belongs to the Santalaceae (Viscaceae) family. This hemiparasitic plant is native to Europe.[3] The most common mistletoe found in India is Dendrophthoe falcata, one of the seven species of Dendropthoe and belongs to the Loranthaceae family. Mistletoe commonly found in China is Taxillus chinensis Danser (mulberry mistletoe). The different mistletoes that are found within Southeast Asia include Scurrula atropurpurea, Scurrula ferruginea, Macrosolen cochinchinensis, Dendrophthoe curvata, Loranthus parasiticus, and Scurrula oortiana.[45678]

Brunei Darussalam, a Southeast Asian nation rich in flora and fauna, has more than 70% of its country made up of primary rainforests, rendering it an excellent resource of a great diversity of plants and wildlife. Three common species of mistletoes found in Brunei are D. curvata, S. ferruginea, and M. cochinchinensis.[9]

BOTANY

All these three mistletoes are aerial hemiparasites and attached to the stems of trees through their haustoria. They derive nutrients and water from the host plants. The green leaves of mistletoes enable the parasitic plants to produce additional food through photosynthesis.[10] Table 2 summarizes the common host plants that these mistletoes parasitize on.

Table 2

Common host plants of the mistletoes

SCURRULA FERRUGINEA

S. ferruginea is a semi-woody plant with slender, pendulous branches that grows up to 70 cm in length. The branches have brown hair on its bark. Being a hemiparasitic plant, it attaches itself to different types of trees such as citrus trees that grow in full sunlight and at times, penetrates into the host plant.[11] The leaves are arranged opposite and elliptically, up to 7 cm by 2.5 cm with a glossy upper surface and lower brownish fuzzy surface.[12] The flowers are inflorescences and arranged in clusters of 4–7, emerging from the axils. Each flower consists of four small petals with brown hair on its 1.5 cm long tubular corolla with dark brown interior. The brown hairy ovary is found within the flower. Due to its slender pendulous nature and rusty colored leaves, S. ferruginea has earned its name as slender busy mistletoe. It is also referred as rusty mistletoe or even scurfy mistletoe. Figure 1a illustrates the parasitic nature of S. ferruginea on a tree along the roadside in Brunei Darussalam. A stalk of S. ferruginea with its brown flower is shown in Figure 1b. S. ferruginea is synonymous with Loranthus ferrugineus and belongs to the Loranthaceae family.[13] In Brunei, S. ferruginea is known as “benalu teh.”

Figure 1

(a) Luscious bush of Scurrula ferruginea on a tree alongside the road in Brunei Darussalam. (b) A stalk of Scurrula ferruginea with the brown flower

DENDROPHTHOE CURVATA

Similar to S. ferruginea, D. curvata belongs to the family of Loranthaceae and is known as rainforest mistletoe or curved mistletoe. The leaves of D. curvata are elliptical. The flowers are usually 3–4.8 cm long of red buds with narrow club-shaped necks that broadened as the flowers curved upward. Within the flower buds, there are flower tubes of about 1.8–3 cm long while the petals curve to one split side of the flower.[7]

MACROSOLEN COCHINCHINENSIS

Another most common species of mistletoe in Brunei Darussalam is M. cochinchinensis. Similarly, this mistletoe belongs to the Loranthaceae family. The flowers of M. cochinchinensis are arranged in groups of six with orange corollas that are straight but inflated in the middle. The flower buds are recognizable by their yellow tips. This shrub mistletoe has gray scattered branches. The leaves are arranged opposite each other and are broadly elliptic, pointed at the ends, and bend upward.[14] Figure 2 displays M. cochinchinensis on a tree.

Figure 2

Macrosolen cochinchinensis parasitizing on a tree

TRADITIONAL AND PHARMACOLOGICAL USES OF MISTLETOES

Although the pharmacological effects of these mistletoes are understudied at the moment, traditional folklore has been using mistletoes for muscle swelling and sprains, bone dislocations and fractures, headaches, postpartum, suspected cancer, and other illnesses.[15] In Nepal, M. cochinchinensis is used for curing headaches.[15] Both M. cochinchinensis and S. ferruginea have been found to have antihypertensive effects exhibited vasorelaxing effects in isolated rat thoracic aorta[1617] and childbirth.[18] S. ferruginea is also used for wounds, snakebites, beriberi, and fever.[18] There is currently no documentation of usage of D. curvata for traditional treatment, but a sibling Dendrophthoe falcata has been documented to possess anticancer, antifertility, antimicrobial, antioxidant, antidiabetic, antihypertensive, antihyperlipidemic, wound healing, and diuretic properties.[1920212223] Nevertheless, there is a thesis published in the Malay language from Indonesia on the effects of D. curvata on breast cancer cell line T47D which postulated that terpenoids from the plants’ extract contributed to the antiproliferative effects.[24] Similarly, there is a lack of documentation on the pharmacological use of M. cochinchinensis, but a recent paper published positive cytotoxic effects of Macrosolen parasiticus on the growth of breast cancer cell line (MCF-7).[25]

Incidentally, among the three mistletoes, most research work has been done on S. ferruginea, which exerted antibacterial, antiviral, antihypertensive, antioxidative, and cytotoxic effects.[26] Table 3 summarizes the various extracts of S. ferruginea and the actions observed from these extracts. The most documented effect of S. ferruginea is its antihypertensive effect. Various (crude methanol, chloroform, and ethyl acetate) extracts of whole plant of S. ferruginea were found to possess vasorelaxant properties on rat thoracic aorta.[16] Applying the methanolic extract of S. ferruginea on Guinea Pig Ileum resulted in hypotensive and spasmogenic effects on the intestinal tract. This observed effect was found to be due to norepinephrine-induced vasoconstriction on the vascular system.[27] Further work by Ameer et al. illustrated that the n-butanol fraction of the methanolic extract is responsible for this antihypertensive effect and this team observed that the rat thoracic aorta relaxed in a dose-dependent hypotensive action by acting on the vascular smooth muscle.[28] In addition, the methanolic extracts also showed antiviral properties against poliovirus.[29] The acetone extract, especially from the stem component of S. ferruginea, contains the most antioxidative property as it scavenges DPPH free radicals[30] The anticancer effects of S. ferruginea are documented using its ethyl acetate fraction of its petroleum ether extract. Quercetin, the active compound in this extract, exerts its anticancer properties against U251, K562, DU145, and MCF-7 cells.[2931] The antimicrobial effects of S. ferruginea aqueous extract against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas putida were observed by Marvibaigi et al.[32] Thus, the extracts of S. ferruginea have shown to exert a wide range of health benefits.

Table 3

Summary of the plausible effects of different extracts of Scurrula ferruginea from the experimental observations

COMPOUNDS FOUND IN MISTLETOES

All these three mistletoes, native Bruneian plants, belong to the family of Loranthaceae. Table 4 summarizes the currently known constituents and their pharmacological studies of Loranthaceae plants. In addition to the chemical constituents stated in Table 4, building blocks such as polypeptides, polysaccharides, glycosides, and steroids that are important for signaling pathways were found in Loranthaceae plants.[173334]

Table 4

Constituents found in Loranthaceae mistletoes and their plausible actions

Isolation of the ethyl acetate fraction of S. ferruginea yielded three flavonol compounds namely: quercetin, quercitrin, and 4”-O-acetylquercitrin. Quercetin was found to kill human glioblastoma cells with an IC50 of 35 μM.[31] A flavanol, quercetin glycosylated with three sugars, was identified from Ligaria cuneifolia Tiegh from Argentina, of the Loranthaceae family. Although the chemical structure of this flavonoid was not reported, the extract consisting of this flavonoid has been found to exert antiproliferative effect on activated cells and enhanced the production of macrophage nitric oxide, an immunomodulant.[35] Therefore, with three different flavonols found in S. ferruginea and a different flavonol component in mistletoe from Loranthaceae family, it is plausible that M. cochinchinensis and D. curvata would possess different types of flavonols.

Alkaloids have been isolated from different mistletoes of the Loranthaceae family, specifically African mistletoe (Tapinanthus dodoneifolius [DC] Danser).[36] However, of the three mistletoes mentioned, isolation of alkaloids has not yet been documented. This is most likely attributed to the lack of studies on these three mistletoes. Another chemical found in a South American Loranthaceae mistletoe, Struthanthus vulgaris, in Southeast Brazil is tannin, a natural polyphenol.[33] Tannins have been found to exert anticancer and antiviral effects.[3738] Another compound found in Loranthaceae mistletoes is terpenoid, an antimicrobial essential oil, which is also used as a food preservative.[40] An example of the mistletoe, in which terpenoids are found in is Loranthus micranthus (Linn) from eastern Nigeria.[39] Gallic acid, a weak carbonic anhydrase inhibitor, is another chemical identified from one of the Loranthaceae mistletoes, Psittacanthus calyculatus, a mistletoe from South America.[41] Gallic acid protects the neurons by its antioxidative activity and consequentially by alpha-synuclein modification leading to amyloid fibrils inhibition alleviates Alzheimer's and Parkinson's diseases.[42] A new flavanocoumarin named loranthin was identified from Plicosepalus acacia, also known as Loranthus acaciea. This compound was found to significantly scavenge free radicals and acts against microbes.[43] Therefore, Loranthaceae mistletoes consist of a wide range of constituents that provide health benefits. Therefore, Loranthaceae mistletoes consist of a wide range of constituents that provide health benefits similar to other medicinal plants and remain a potential niche for cancer therapies.[44].

CONCLUSION AND FUTURE PROSPECTS

The deficiency of research on both M. cochinchinensis and D. curvata has left pervasive documentation lacuna. Although there are few research articles mostly on antihypertensive effect of S. ferruginea, more research needs to be done to elucidate various constituents and their effects. The web of cross-relationships needs to be carefully studied both qualitatively and quantitatively. The compounds identified and isolated from these plants are keys for the exploration of biological activities of their extract, which are clues given by nature about their potential in health care. Extrapolation of results from other species of these genera may also assist in the identification and exploration of various pharmacological effects, as it is presumed that similar genera would have identical effects. Constituents-based research and documentation would pave the way for identifying and quantifying the beneficial uses of the extracts leading to clinical trials. Thus, the need of the hour for these plants is high-quality research to benefit humanity. In conclusion, the three Loranthaceae mistletoes found in Borneo region are still awaiting further studies for exploration of the health benefits they bring. There is potential in the medicinal values of these plants.

Financial support and sponsorship

This work was supported by Brunei Research Council 6 grant (UBD/BRC/6).

Conflicts of interest

There are no conflicts of interest.