A review on traditionally used South African medicinal plants, their secondary metabolites and their potential development into anticancer agents

ETHNOPHARMACOLOGICAL RELEVANCE : Approximately 70% of anticancer drugs were developed or derived from natural products or plants. Southern Africa boasts an enormous floral diversity with approximately 22,755 plant species with an estimated 3000 used as traditional medicines. In South Africa more than 27 million individuals rely on traditional medicine for healthcare. The use of South African plants for the treatment of cancer is poorly documented, however there is potential to develop anticancer agents from these plants. Limited ethnobotanical studies report the use of plants for cancer treatment in traditional medicine. Plants growing in tropical or subtropical regions, such as in South Africa, produce important secondary metabolites as a protective mechanism, which could be used to target various factors that play a key role in carcinogenesis. AIMS : The aim was to collate information from primary ethnobotanical studies on South African plants traditionally used for the treatment of cancer. Evaluation of literature focused on traditionally used plants that have been tested for their in vitro activity against cancer cells. Secondary metabolites, previously identified within these plant species, were also included for discussion regarding their activity against cancer. The toxicity was evaluated to ascertain the therapeutic potential in further studies. Additionally, the aim was to highlight where a lack of reports were found regarding plant species with potential activity and to substantiate the need for further testing. MATERIALS AND METHODS : A review of ethnobotanical surveys conducted in South Africa for plants used in the treatment of cancer was performed. Databases such as Science Direct, PubMed and Google Scholar, university repositories of master's dissertations and PhD theses, patents and books were used. Plant species showing significant to moderate activity were discussed regarding their toxicity. Compounds identified within these species were discussed for their activity against cancer cells and toxicity. Traditionally used plants which have not been scientifically validated for their activity against cancer were excluded. RESULTS : Twenty plants were documented in ethnobotanical surveys as cancer treatments. Numerous scientific reports on the potential in vitro activity against cancer of these plants and the identification of secondary metabolites were found. Many of the secondary metabolites have not been tested for their activity against cancer cells or mode of action and should be considered for future studies. Lead candidates, such as the sutherlandiosides, sutherlandins, hypoxoside and pittoviridoside, were identified and should be further assessed. Toxicity studies should be included when testing plant extracts and/or secondary metabolites for their potential against cancer cells to give an indication of whether further analysis should be conducted. CONCLUSION : There is a need to document plants used traditionally in South Africa for the treatment of cancer and to assess their safety and efficacy. Traditionally used plants have shown promising activity highlighting the importance of ethnobotanical studies and traditional knowledge. There are many opportunities to further assess these plants and secondary metabolites for their activity against cancer and their toxic effects. Pharmacokinetic studies are also not well documented within these plant extracts and should be included in studies when a lead candidate is identified.The National Research Foundation (SARCHI)http://www.elsevier.com/locate/jethpharmhj2021Plant Production and Soil Scienc

Evaluation of traditionally used medicinal plants for anticancer, antioxidant, anti-inflammatory and anti-viral (HPV-1) activity

The aim of this study was to determine the anticancer, antioxidant, anti-inflammatory and antiviral activities of traditionally used medicinal plants.The extracts were tested for cytotoxicity against human melanoma (A375), epidermoid carcinoma (A431), cervical epithelial carcinoma (HeLa) and human embryonic kidney cells (HEK-293). The antioxidant and anti-inflammatory activities were also determined. Gomphocarpus fruticosus, Helichrysum kraussii and Syzygium jambos were selected for activity against the herpes simplex virus type-1.The extracts exhibited low toxicity towards HEK-293 cells, and four extracts; namely Acacia mellifera, G. fruticosus, H. kraussii and S. jambos, were able to inhibit the A431 and HeLa cells with 50% inhibitory concentrations (IC50) ranging from 34.90-56.20μg/ml. Arbutus unedo, Combretum molle, Dissotis princeps, Erythrophleum lasianthum, Harpephyllum caffrum, H. kraussii and S. jambos, showed high DPPH inhibitory activity, with IC50 values ranging from 2.41-5.25μg/ml. The highest antioxidant activity was seen for S. jambos (DPPH) and A. unedo (NO) respectively with greater activity than ascorbic acid. D. princeps, H. caffrum, Leucas martinicensis and S. jambos, showed high inhibition of the cyclooxygenase-2 (COX-2) enzyme with IC50 values ranging from 3.79-25.80μg/ml with S. jambos showing the highest activity. S. jambos further showed the highest anti-HSV-1 activity at 50.00μg/ml against 100TCID50virus challenge dose.This is the first report of the selected plants for their cytotoxicity, anti-inflammatory and viral inhibitory activity. S. jambos was able to show high inhibition of the HPV type-1 virus and the COX-2 enzyme.The National Research Foundation of South Africa (84870), the University of Pretoria and the Department of Science and Technology. Walter Sisulu National Botanical Gardens (SANBI).http://www.elsevier.com/locate/sajb2018-09-30hj2017Plant Production and Soil Scienc

Mupirocin promotes wound healing by stimulating growth factor production and proliferation of human keratinocytes

Mupirocin has been reported for its role in the treatment of infected wounds through its antibacterial activity, however the role of mupirocin in promoting wound healing via alternative mechanisms has not been extensively evaluated. This study aimed to evaluate the potential effect of mupirocin to promote wound healing, not only through its antibacterial activity but by increasing human keratinocyte proliferation and growth factor production. In the scratch assay, using human keratinocytes (HaCat), mupirocin (at 0.1 and 0.2 mM) significantly increased wound closure compared to the vehicle control. Cell viability, measured from the scratch assay, verified the increase in wound closure, where mupirocin at both concentrations showed higher cell viability compared to the vehicle control. In addition, mupirocin at 0.1 mM significantly stimulated the production of hepatocyte growth factor and M-CSF in HaCat cells, whereas at 0.2 mM, PDGF-AA and EPO were increased. The findings of this study suggest that mupirocin, which is commonly used as an antibacterial agent for the treatment of wounds, also facilitates the wound healing process by stimulating the proliferation of human keratinocytes and enhancing the production of several growth factors involved in wound healing. This is the first report on the effect of mupirocin on growth factors expressed by human keratinocytes as well as the stimulation of keratinocyte proliferation.The National Research Foundation and Department of Science Innovation South African Research Chairs Initiative (SARChI).https://www.frontiersin.org/journals/pharmacologydm2022BiochemistryGeneticsMicrobiology and Plant PathologyPlant Production and Soil Scienc

The effect of Helichrysum odoratissimum (L.) sweet on cancer cell proliferation and cytokine production

The cytotoxicity of Helichrysum odoratissimum against human epidermoid carcinoma (A431), malignant melanoma (A375), cervical epithelial carcinoma (HeLa) and human embryonic kidney (HEK-293) cells was investigated. The cytokine production and antioxidant activity was also determined. H odoratissimum was selected based on its traditional usage as a dressing for wounds. In this study the cytotoxicity was performed on skin and cervical cancer which are associated with the presence of wounds. H. odoratissimum showed inhibitory activity against A431 cells, with a fifty percent inhibitory concentration (IC50) of 15.5±0.2 μg/ml, and a high DPPH inhibition with an IC50 of 5.13±0.07 μg/ml. A431 cells treated with the extract showed an increase in morphological characteristics associated with apoptosis. The extract induced IL-12 in U937 cells and inhibited IL-8 at the tested concentrations, with the highest levels being 12.4±7 pg/ml and 103±6.1 pg/ml respectively. IL-2 was inhibited by 56 % and 52 % in naive and PHA induced murine splenocytes respectively. Furthermore, 2 lipophilic fractions and 3 compounds were isolated from the extract. The lipophilic fractions showed relative cytotoxicity on A431 cells with IC50 values of 175±13.5 μg/ml and 61.3±0.16 μg/ml. The extract showed significant hepatoprotection at 25 μg/ml on HepG2 cells exposed to D-Galactosamine. This is the first report of the activity of H. odoratissimum ethanolic leaf stem extract on A431, A375, HeLa and HEK-293 cell lines as well as the isolation of two promising lipophilic fractions.The University of Pretoria, the National Research Foundation and the Department of Science and Technology.http://ijppr.comam2018Plant Production and Soil Scienc

The activity of Aloe arborescens Miller varieties on wound-associated pathogens, wound healing and growth factor production

Various Aloe L. species have been used worldwide to soothe and treat dermal wounds and burns. However, there is a lack of substantiative research on the efficacy of Aloe L. species for wound healing. The aim of this study was to investigate the differences in biological activities of the gel and ethanolic (EtOH) leaf extracts of seven Aloe arborescens Miller varieties. The extracts were investigated for their antibacterial activity against wound-associated bacteria, Staphylococcus aureus (ATCC 6538 and ATCC 25293) and Pseudomonas aeruginosa (ATCC 9027), as well as their nitric oxide (NO) scavenging potential. Varieties with antibacterial activity were further evaluated for wound closure and growth factor stimulation in human keratinocytes (HaCaT). The EtOH leaf extract of the ‘Eloff’ and ‘Jack Marais’ varieties displayed antibacterial activity against S. aureus ATCC 25293 (MIC of 500 and 250 μg/mL, respectively). The EtOH leaf extract of ‘Jack Marais’ displayed an MIC of 500 μg/mL against S. aureus ATCC 6538. The gel extract of ‘Le Roux’ exhibited antioxidant activity with a half maximal inhibitory concentration (IC50 of 2696 ± 582.66 μg/mL). The EtOH leaf extracts of ‘Eloff’ and ‘Jack Marais’ showed significant (p < 0.05) wound closure of 56.06 ± 1.47 and 73.72 ± 0.65%, respectively at 50 μg/mL and the ‘Jack Marais’ gel extract significantly stimulated wound closure (p < 0.05) by 77.02 ± 1.97 and 71.51 ± 1.11% at 50 and 100 μg/mL, respectively. Both the ‘Jack Marais’ gel extract (at 50 and 100 μg/mL) and the EtOH leaf extract (50 μg/mL), significantly (p < 0.05) increased platelet-derived growth factor (PDGF-AA) secretion to 601.09 ± 97.77, 1035.00 ± 913.98 and 559.43 ± 112.52 pg/mL, respectively. The ‘Jack Marais’ EtOH leaf extract exhibited the highest antibacterial activity, whereas the gel extract displayed the greatest potential to stimulate wound closure. This not only suggests a difference in biological activity among varieties but also between the type of extract (gel or leaf).The National Research Foundation of South Africa and by the Department of Science and Innovation (DSI), the Technology Innovation Agency (TIA) and South African Research Chairs Initiative (SARChI).http://www.elsevier.com/locate/sajb2023-06-16hj2023BiochemistryGeneticsMicrobiology and Plant PathologyPlant Production and Soil Scienc

THERAPEUTIC POTENTIAL OF GNIDIA CAPITATA L. F.: INVESTIGATIONS ON ITS ANTITYROSINASE, ANTIBACTERIAL, ANTIOXIDANT AND ANTICANCER ACTIVITIES

Background: Gnidia capitata L. F. belongs to the family Thymelaeaceae, and has been widely reported for its ethnobotanical uses, especially for the treatment of several human ailments which include skin conditions. However, there is limited information about the pharmacological properties of this plant as a potential cosmetic agent or pharmaceutical. The aim of this study was to evaluate the therapeutic potential of G. capitata for its anti-tyrosinase, antibacterial, antioxidant, anticancer and anti-mycobacterial properties. Materials and methods: G. capitata was extracted with methanol (MeOH), ethyl acetate (EtOAc), dichloromethane (DCM) and hexane (n-Hex). All extracts were tested in vitro for activities against Propionibacterium acnes (ATCC 11827) and Mycobacterium tuberculosis H37Rv (ATCC 27294). Tyrosinase inhibitory activity was screened using tyrosinase from Agaricus bispor. Antioxidant activity was investigated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Results: EtOAc, DCM and n-Hex extracts of the plant showed antibacterial activity against P. acnes with MICs of 125 μg/ml. The DCM and n-Hex extracts showed anti-mycobacterial activity with MICs of 500μg/ml. The methanolic extract showed the highest antioxidant activity with an IC50 of 41.83μg/ml. Conclusion: The findings presented in this study may explain the potential use of G. capitata for the treatment of certain skin conditions. The potent antioxidant activity could help control the negative effects associated with inflammatory mediators that are produced during the immune response in people that are affected by skin conditions

Evaluation of wound healing and antibacterial potential of Greyia radlkoferi Szyszyl. Ethanolic leaf extract

Angiogenesis is an essential mechanism in both physiological and pathological functions, such as wound healing and cancer metastasis. Several growth factors mediate angiogenesis, including vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). This study evaluated the potential wound healing activity of Greyia radlkoferi Szyszyl (GR) and its effect on growth factors regulating angiogenesis. The ethanolic leaf extract of GR was evaluated for antibacterial activity against wound associated bacteria; Staphylococcus aureus and Pseudomonas aeruginosa. It exhibited antibacterial activity against two strains of S. aureus (ATCC 25293 and ATCC 6538) displaying a minimum inhibitory concentration (MIC) at 250 and 500 μg/ ml, respectively. The antioxidant activity of the extract was investigated for nitric oxide (NO) scavenging activity and showed a fifty percent inhibitory concentration (IC50) of 1266.5 ± 243.95 μg/ml. The extract was further investigated to determine its effect on the proliferation and modulation of growth factors secreted by human keratinocytes (HaCaT). Its effect on wound closure was evaluated using the scratch assay, where non-toxic concentrations were tested, as determined by the antiproliferative assay against HaCat cells (IC50 > 400 μg/ml). Results showed that the extract significantly inhibited wound closure, with a percentage closure of 60.15 ± 1.41% (p < 0.05) and 49.52 ± 1.43% (p < 0.01) at a concentration of 50 and 100 μg/ml, respectively, when compared to the 0.25% Dimethyl sulfoxide vehicle control (65.86 ± 1.12%). Quantification of secreted growth factors from cell-free supernatant, collected from the scratch assay, revealed that the extract significantly decreased the concentration of platelet-derived growth factor (PDGF-AA) at both 50 (p < 0.05) and 100 μg/ml (p < 0.001) (443.08 ± 77.36 and 178.98 ± 36.60 pg/ml) when compared to the 0.25% DMSO vehicle control (538.33 ± 12.64 pg/ml). Therefore, whilst the extract showed antibacterial activity against wound associated bacteria, it did not induce wound healing but rather showed a significant inhibition of wound closure, which was confirmed by the inhibition of PDGF-AA, a major growth factor involved in angiogenesis. Therefore, the GR extract, should be considered for further investigation of anti-angiogenic and anti-metastatic properties against cancer cells.The Department of Science and Innovation (DSI), the Technology Innovation Agency (TIA) and South African Research Chairs Initiative (SARChI).https://www.frontiersin.org/journals/pharmacologydm2022Plant Production and Soil Scienc

Antiproliferative Activity of Buddleja saligna (Willd.) against Melanoma and In Vivo Modulation of Angiogenesis

Funding Information: This research was funded by the University of Pretoria, the National Research Foundation-DAAD (SFD13080220333), the Department of Science and Innovation (DST/CON 0059/2019), the Innovation Hub, L’Oréal-UNESCO and FCT-MCTES (UIDP/04378/2020 and UIDB/04378/2020). Publisher Copyright: © 2022 by the authors.Melanoma cells secrete pro-angiogenic factors, which stimulates growth, proliferation and metastasis, and therefore are key therapeutic targets. Buddleja saligna (BS), and an isolated triterpenoid mixture (DT-BS-01) showed a fifty percent inhibitory concentration (IC50) of 33.80 ± 1.02 and 5.45 ± 0.19 µg/mL, respectively, against melanoma cells (UCT-MEL-1) with selectivity index (SI) values of 1.64 and 5.06 compared to keratinocytes (HaCat). Cyclooxygenase-2 (COX-2) inhibition was observed with IC50 values of 35.06 ± 2.96 (BS) and 26.40 ± 4.19 µg/mL (DT-BS-01). BS (30 µg/mL) significantly inhibited interleukin (IL)-6 (83.26 ± 17.60%) and IL-8 (100 ± 0.2%) production, whereas DT-BS-01 (5 µg/mL) showed 51.07 ± 2.83 (IL-6) and 0 ± 6.7% (IL-8) inhibition. Significant vascular endothelial growth factor (VEGF) inhibition, by 15.84 ± 4.54 and 12.21 ± 3.48%, respectively, was observed. In the ex ovo chick embryo yolk sac membrane assay (YSM), BS (15 µg/egg) significantly reduced new blood vessel formation, with 53.34 ± 11.64% newly formed vessels. Silver and palladium BS nanoparticles displayed noteworthy SI values. This is the first report on the significant anti-angiogenic activity of BS and DT-BS-01 and should be considered for preclinical trials as there are currently no US Food and Drug Administration (FDA) approved drugs to inhibit angiogenesis in melanoma.publishersversionpublishe

Cannabidiol-mediated green synthesis, characterization, and cytotoxicity of metal nanoparticles in human keratinocyte cells

This study investigated a unique one-pot microwave- assisted green synthesis method of gold (Au) and silver (Ag) nanoparticles (NPs) using cannabidiol (CBD) as a capping and reducing agent. Furthermore, Au and Ag NPs were also chemically synthesized using poly(vinyl pyrrolidone), which functioned as reference materials when comparing the size, shape, and cytotoxicity of NPs. Synthesis parameters such as reaction time, temperature, and precursor molar ratio were optimized to control the size and shape of the biosynthesized NPs. Various characterization techniques such as transmission electron microscopy, ultraviolet−visible spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction were used to confirm the formation and properties of Au and Ag NPs. Both biosynthesized metal NPs were spherical and monodispersed, with average particle sizes of 8.4 nm (Au-CBD) and 4.8 nm (Ag-CBD). This study also explored the potential cytotoxicity of CBD-capped NPs in human keratinocyte cells, which was observed to be of minimal concern. The novel synthesis approach presented in this study is free from harsh chemical reagents; therefore, these NPs can be used in a wide array of applications, including the pharmaceutical and biomedical fields.The Department of Science and Innovation and the Council for Scientific and Industrial Research.http://pubs.acs.org/journal/acsodfam2022PharmacologyPlant Production and Soil Scienc

Cytotoxicity of syringin and 4-methoxycinnamyl alcohol isolated from Foeniculum vulgare on selected human cell lines

The present study was carried out to determine the cytotoxic effect of seven plant extracts and the isolated compounds; syringin and 4-methoxycinnamyl alcohol on cancerous and non-cancerous cells. The ethanol extract of F. vulgare was found to exhibit the most significant toxicity with an IC50 value of 19.97 μg/mL on HeLa cells. Bioassay guided fractionation lead to the isolation of two compounds, syringin (1) and 4-methoxycinnamyl alcohol (2). Both compounds showed toxicity against MCF-7, HeLa, and DU145 cancer cell line. The results showed that compound 2 showed high toxicity against all the cancer cell lines with IC50 values of 14.24, 7.82 and 22.10 μg/mL, respectively. 4-Methoxycinnamyl alcohol also showed no apoptotic effect in cell cycle analysis after 48 hours at a concentration of 10 μg/mL. However DNA fragmentation study revealed that, necrosis took place at a concentration of 10 μg/mL after 48 h exposure.http://www.tandfonline.com/loi/gnpl202016-09-15hb201