Clinacanthus nutans is a species of plant in the family Acanthaceae. It is also known by the common names belalai gajah Malay , phaya yo Thai , Sabah snake grass , ki tajam Sunda , and dandang gendis Jawa. This plant is used in the traditional herbal medicines of Malaysia, Indonesia, Thailand, and China. Clinacanthus nutans is a herbaceous plant that grows in low shrubs up to 2.

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The datasets analyzed during the current study are available from the corresponding author on reasonable request. Clinacanthus nutans Burm. However, scientific evidence is generally lacking to support this traditional claim. This study aims to investigate the in vitro, ex-vivo and in vivo effects of C. The in vitro anti-angiogenic effects of C.

Besides, the rat aortic ring and chick embryo chorioallantoic membrane CAM assays, representing ex vivo and in vivo models, respectively, were performed. The MTT assay revealed that water extract of C. Therefore, the water extract was chosen for subsequent experiments. However, the water extract failed to suppress HUVEC transmigration, differentiation and permeability. Importantly, C. In conclusion, these findings reveal potential anti-angiogenic effects of C.

Angiogenesis is the main contributor to the transition of pre-invasive and dormant tumour cells to a more invasive and malignant cells, through establishing additional blood vessel network from pre-existing vasculature to enable more efficient oxygen and nutrient delivery for growth.

Such pathologic event is orchestrated by overexpression of vascular endothelial growth factor VEGF secreted by tumour cells, the known factor that promotes endothelial cell proliferation, invasion, migration and capillary tube formation [ 1 ]. Hence, inhibition of tumour angiogenesis by targeting VEGF pathway has emerged as an important strategy in combating cancers [ 2 ]. However, the new blood vessels formed are unlike normal blood vessels; they exhibit increased permeability, and cause diminished blood flow and create hypoxic microenvironment within the tumour [ 3 ].

To date, not more than 15 identified anti-cancer drugs that target tumour angiogenesis are granted approval from US Food and Drug Administration. In addition to undesirable side effects and low patient survival, those agents often couple with low therapeutic efficacy and high risk of drug resistance after long-term treatment, as reported in trials involving small cell lung cancer patients treated with bevacizumab and sunitinib [ 4 ].

The current anti-angiogenic drugs are single-target based agents which often could not achieve desired outcomes from inhibiting angiogenesis, mainly because of the redundancy in the angiogenic pathways. Traditional plant extracts are source of multi-targeted therapeutic agents as they contain various medicinal phytochemicals. The production cost is usually low due to their abundance in nature. Plant extracts may also reduce the risk of adaptive resistance that is commonly seen in therapy with single agent [ 3 ].

Previous studies have reported that C. Ethanol extract of C. Researchers have also demonstrated that C. Despite claims regarding the use of C.

Here we showed that C. Growth factor-reduced matrigel was purchased from BD Bioscience. Whole plant of Clinacanthus nutans Burm.

The plant was verified by Dr. The specimen of C. Briefly, the plant was harvested, cleaned with water, dried and separated into leaves and stems. The leaves were then dried at room temperature under the shade in a well-ventilated room and ground to fine powder. HUVECs between passage three to six were used in the experiments. Cell proliferation assay was performed as described previously by Mosmann [ 12 ], with some modifications. HUVECs were plated onto well plates at a cell density of 1.

The assay was carried out according to Kavitha et al. HUVECs were plated onto 6-well plates and allowed to grow until confluence. The cell migration was quantified using the formula: Initial wound distance minus final wound distance divided by two [ 13 ]. Tube formation method was performed according to Arnaoutova and Kleinman [ 14 ]. HUVECs 1. Next, the monolayers were treated with different concentrations of C. The treatments were replaced daily.

Growing sprouts, at day 8, were photographed with an inverted microscope Olympus , and the sprout length was analysed by Image J NIH software program. Fertilized chicken eggs were purchased from a poultry farm Hing Hong Sdn. The CAM assay was performed according to West et al. The needle hole was then sealed with clear tapes. Subsequently, a small window was carefully created on the top-most surface of the eggshells.

The windows were then covered by sterile parafilm and the eggs were placed back into the oven. After that, the windows were sealed by a sterile parafilm and the eggs were placed back into the oven. Angiogenesis levels were determined by counting the number of vessels contacted to C.

Extraction of C. At a lower C. These data suggest that the water soluble compounds within the C. We then tested the C. However, water extract of C. The water extract of C. VEGF is the known driver of endothelial cell proliferation within tumour microenvironment condition [ 18 ]. As expected, with increasing concentration of C. These findings suggest the water extract could suppress endothelial growth in dose-dependent manner. Effect of C. Next, we examined the effects of ethanol and water extract of C.

Again, no inhibitory effect was observed in ethanol extract-treated group. Representative width was photographed. These results suggest that water extract of C. Representative width were photographed. Endothelial cell migration is known to be driven by VEGF gradient [ 19 ]. A Boyden chamber assay, which creates VEGF gradient between the upper and lower chambers, was used to investigate effect of C.

As shown in Fig. However, this event was not reversed by C. Representative results were shown. It is known that a complex endothelial tubular network can be formed when endothelial cells were cultured in three dimensions Matrigel bed in the presence of VEGF [ 20 ], and such event can be disrupted by Suramin, a drug which is commonly used in treating sleeping sickness and river blindness [ 21 ].

To examine if the water extract of C. However, no suppressive effect was observed in all C. The endothelial permeability, measured by fluorescent unit relative to the amount of fluorescein isothiocyanate FITC -dextran which passes through the cell monolayer, showed that C. Nonetheless, all doses of C. These data indicate that C. To investigate the effect of C. In the control, the non-stimulated aortic rings exhibited a sprout area of 1.

Similar to the tube formation assay, the aortic ring sprouting effect was improved to 1. We then tested this effect in an in vivo CAM model, and observed the similar capability in C.

These results suggest that C. Tumour angiogenesis is one the main contributing factors that promotes tumour progression.

Thus, targeting the blood supply may limit its growth and progression [ 23 ]. However, simultaneous targeting of multiple aspects may be required to achieve robust antiangiogenic response. This multi-targeted effect can be achieved by using combinations of drugs, or from natural medicinal herb extracts which possess various active ingredients. Whilst more scientific evidence is needed to conclude its therapeutic use, our previous study has also shown that the C.

Here, we demonstrated the potential of C. Under physiological conditions, endothelial cell migration is coordinated by cytoskeleton reorganization where protrusions formed by lamellipodia direct the migrating cells, and this is followed by contraction of stress fibres which allows the cell body to move forward [ 24 ]. This dynamic and tightly regulated process, however, is disrupted during tumour angiogenesis, resulting in excessive cell migration and proliferation, the pivotal processes that eventually leads to structure tube and microvessel morphogenesis.

In this study, we showed that these processes can be inhibited by C. We also tested the effect of the extracts and confirmed their efficacy even in the presence of human VEGF , the most abundant and active isoform of VEGF-A monomer [ 24 ], which mediates angiogenesis within tumour microenvironment [ 25 ]. Taken together, our data support the notion that the water extract of C. Endothelial cell migration also depends on the existence of a VEGF gradient, which serves as an attractant and regulates the motion of the endothelial tip cell [ 19 ].

The Boyden chamber assay demonstrated that C. However, Boyden chamber model is mainly involved in migration process, thus, this indicate extracts not be able to suppress endothelial migration. Vascular hyperpermeability is a hallmark of acute inflammation, a pathologic event that responsible for oedema and coronary heart diseases [ 28 ].

In cancers, chronic vessel hyperpermeability may facilitate leukocyte infiltration into the tumour, promote metastatic spread of cancer cells [ 29 ], and impaired efficient drug delivery due to increased interstitial pressure [ 30 ]. Drugs which capable to normalize tumour vasculature and attenuates the exaggerated permeability has emerged to be a new concept in anti-angiogenic therapy [ 31 ].

Normalization of abnormal vasculature able to increase the efficacy of conventional therapies and decrease the rate of metastasis even though it makes the vasculature to be more efficient for oxygen delivery towards the tumour [ 31 ].


Associated Content

Context: Medicinal plants have attracted global attention for their hidden therapeutic potential. Clinacanthus nutans Burm. CN contains phytochemicals common to medicinal plants, such as flavonoids. Traditionally, CN has been used for a broad range of human ailments including snake bites and cancer. Objectives: This article compiles the ethnomedicinal uses of CN and its phytochemistry, and thus provides a phytochemical library of CN. It also discusses the known pharmacological and biological effects of CN to enable better investigation of CN. Methods: This literature review was limited to articles and websites published in the English language.


Clinacanthus nutans Burm. Lindau Acanthaceae , commonly known as Sabah snake grass, is a vegetable and a well-known herb that is considered an alternative medicine for insect bites, skin rashes, herpes infection, inflammation, and cancer and for health benefits. Current review aims to provide a well-tabulated repository of the phytochemical screening, identification and quantification, and the pharmacological information of C. This review has documented valuable data obtained from all accessible library databases and electronic searches. For the first time we analyzed the presence of flavonoids, triterpenoids, steroids, phytosterols, and glycosides in C. Phytochemical quantification further illustrated that C.


The datasets analyzed during the current study are available from the corresponding author on reasonable request. Clinacanthus nutans Burm. However, scientific evidence is generally lacking to support this traditional claim. This study aims to investigate the in vitro, ex-vivo and in vivo effects of C. The in vitro anti-angiogenic effects of C.


Clinacanthus nutans has had a long history of use in folk medicine in Malaysia and Southeast Asia; mostly in the relief of inflammatory conditions. In this study, we investigated the effects of different extracts of C. Extracts of leaves and stem bark of C. The extracts were standardized by determining its total phenolic and total flavonoid contents.

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