African medicinal plants and their derivatives: Current efforts towards potential anti-cancer drugs

African medicinal plants and their derivatives: Current efforts towards potential anti-cancer drugs

Accepted Manuscript African medicinal plants and their derivatives: Current efforts towards potential anti-cancer drugs Mzwandile M. Mbele, Rodney R...

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Accepted Manuscript African medicinal plants and their derivatives: Current efforts towards potential anti-cancer drugs

Mzwandile M. Mbele, Rodney R. Hull, Zodwa Z. Dlamini PII: DOI: Reference:

S0014-4800(17)30127-2 doi: 10.1016/j.yexmp.2017.08.002 YEXMP 4070

To appear in:

Experimental and Molecular Pathology

Received date: Revised date: Accepted date:

8 March 2017 19 July 2017 7 August 2017

Please cite this article as: Mzwandile M. Mbele, Rodney R. Hull, Zodwa Z. Dlamini , African medicinal plants and their derivatives: Current efforts towards potential anticancer drugs. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yexmp(2017), doi: 10.1016/j.yexmp.2017.08.002

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ACCEPTED MANUSCRIPT African medicinal plants and their derivatives: Current efforts towards potential anticancer drugs Mzwandile M. Mbele, Rodney R. Hull and *Zodwa Z. Dlamini Research, Innovation & Engagements Portfolio, Mangosuthu University of Technology, Durban, 4031, South Africa

*Corresponding Author: Mangosuthu University of Technology, Research, Innovation &

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Engagements Portfolio, Durban, 4031, South Africa

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Email: [email protected]/ [email protected]

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Abstract Cancer is a leading cause of mortality and morbidity worldwide and second only to cardiovascular diseases. Cancer is a challenge in African countries because generally there is limited funding available to deal with the cancer epidemic and awareness and this should be prioritised and all possible resources should be utilized to prevent and treat cancer. The

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current review reports on the role of African medicinal plant in the treatment of cancer, and also outlines methodologies that can also be used to achieve better outcomes for cancer treatment.

This

review

outlines

African

medicinal plants,

isolated

compounds

and

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technologies that can be used to advance cancer research. Chemical structures of isolated

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compounds have an important role in anti-cancer treatments; new technologies and methods may assist to identify more properties of African medicinal plants and the treatment of

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cancer. In conclusion, African medicinal plants have shown their potential as enormous resources for novel cytotoxicity compounds. Finally it has been noted that the cytotoxicity

Keywords:

cancer,

apoptosis,

medicinal

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angiogenesis

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depends on the chemical structural arrangements of African medicinal plants compounds. plants,

mitochondrial

membrane

potential,

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1. Introduction Cancer is a leading cause of mortality and morbidity worldwide after cardiovascular diseases (Banydeen et al, 2015; Cheung and Delfabbro, 2016). Cancer is defined as the uncontrolled proliferation of cells due to the inhibition of apoptotic processes. According to the

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International Agency for research on Cancer, it is estimated that worldwide new cases of cancer will reach 14.1 million and the number of deaths in these cases will reach 8.2 million (Cheung and Delfabbro, 2016; Cancer IAfRo, 2014). The major problem with cancer cells

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are their inability to undergo apoptosis due to unidentified mutations that result in an

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accumulation of cancer cells, which finally migrate, to other parts of the body. It has been also reported that cancer is a critical public health problem in Africa (Kuete, 2013; Kuete and

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Efferth, 2015).

One of the reasons cancer is a major problem in African countries is that generally there is

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limited funding available to deal with the cancer epidemic and lack of awareness and this should be prioritised and all possible resources should be utilized to prevent and treat cancer

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(Kuete and Efferth, 2015). In Africa, there is high increase in the burden of cancer due to aging and growth in the population and also an increase in the prevalence of risk factors, which are associated with economic transition (Jemal et al, 2012). These risk factors include

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smoking; obesity; physical inactivity and reproductive behaviours (Jemal et al, 2012; Boyle and Levin, 2008). Despite the large increase in the burden of cancer in Africa, less effort is expended in combating this increase due to the lack of resources and other pressing health

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problems. Africa is facing the same problems with communicable diseases such as tuberculosis; malaria and HIV AIDS (Jemal et al, 2012; Parkin et al, 2008; Sitas et al, 2008).

New cases of cancer in African countries have been estimated to be between 542,000 and 715,000 in 2008. It has also been estimated that new cases will reach 15 million worldwide by the year 2020 of which 70% will be in developing countries where governments are not prepared to engage with cancer burden and where the survival rates are less than half of those in more developed countries. There is a variation in incident and mortality, which depends on social, cultural and environmental exposure. This variation also depends on the type of cancer most prevalent in the region (Kuete and Efferth, 2015; Jemal et al, 2012).

ACCEPTED MANUSCRIPT Due to the increase in this public health problem, African people have chosen to take alternative medicine from traditional healers so that they can fight these diseases, because they cannot afford Western medicine. Most of their medicines are from natural products (plants), they take plants’ bark; leaves, or roots and dissolve them in boiled water and treat these diseases orally or apply the mixture to wounds and this practice is common in Africa. This shows the importance of natural products in African countries. Even when looking at

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pharmaceuticals worldwide, most medicines are derived from plants. The main aim of this review is to discuss the role of African medicinal plants and their

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derivatives in cancer diseases; the mechanisms involving medicinal plants to treat cancer,

2. Cancer cells and multi-drug resistance.

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achievements so far and areas that require attention for research.

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Cancer is caused by multiple genetic and epigenetic changes leading to abnormal expression of genes involved in initiation, progression and propagation of carcinogenesis (Holmes et al,

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2007). Cancer cells sometimes acquire resistance to drugs due to the presence of adenosine triphosphate binding cassette (ABC) transporters (Shen et al, 2011) the oncogene epidermal growth factor receptor (EGFR) (Kuete and Efferth, 2015; Efferth et al, 2003) and the

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deletions or inactivation of tumour suppressor gene p53 (Kuete and Efferth, 2015; el-Deiry, 1997). This implies that greater efforts should be made in order to identify new anti-cancer

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agents. If these are to be found by screening the extracts from traditional medicinal plants, many more plant extracts and their derivatives must be screened and some modifications in the protocols must be performed in order to assist in overcoming cancer resistance to anti-

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cancer drugs.

3. African medicinal plants and disease treatment Africa has a rich floral and cultural diversity, both of which are important in the development of new drugs based on traditional medicine (Light et al, 2005; Berrington and Lall, 2012). Species uniqueness, variety and diverse ecosystems are all found in Africa (Kuete and Efferth, 2015). Species richness can be viewed in vast longitudinal zones with the highest species diversity being in the central tropical zone. The winter-rainfall Mediterranean climate regions of Northern Africa and the Southern Cape are also rich in species diversity (Kuete and Efferth, 2015).

The number of compounds isolated from African plants that are

interesting in terms of their bio-availability and drug-likeness can be grouped by geographic

ACCEPTED MANUSCRIPT region where the plants were collected from (Figure 1). Most of the compounds of biological importance were isolated from plants collected from Central Africa (35%) followed by South Africa (23%); East Africa (21%) and finally by Northern Africa (Ntie-Kang et al, 2013).

In some cases these compounds isolated from African plants were identified as compounds of biological interest through the use of computer aided techniques. These are models that are used to predict what structure a drug should have in order to target a specific molecule,

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pathway or disease. These predictions are based on ligand docking, pharmacophore searching, neural networking and binding free energy calculations towards a receptor of

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interest. The reason behind these approaches is to stimulate the interaction between potential

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drug and protein receptors of interest (Kubinyi, 1998). Currently investigations towards African medicinal plants are based on random selection of plant extracts based on the

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information identified from ethnobonical uses of the plant (Wachtel-Galor and Benzie, 2011. It may be important to use computer aided mechanisms to select potential medicinal plants to be screened. These methods will foster efforts towards lead optimization and facilitate the

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entry of the most interesting compounds into clinical trials (Ntie- Kang et al, 2013).

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4. Medicinal plants and their derivatives in the treatment of cancer Worldwide there is a history of using plants to supply food; fuel; cosmetics and medicine. It

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is estimated that 90% of the African population are still dependent on traditional medicine Wachtel-Galor and Benzie, 2011). It has been reported that Southern Africa has a large number of indigenous plant medicines, which have been used as alternative medicine for

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many years (Van Wyk, 2015). Almost 65% of all anticancer drugs are derivatives of natural compounds isolated from sources such as plants and marine organisms (Balunas and Kinghorn, 2005. The plant derivatives are known as secondary metabolites, and aid the plant to grow. The secondary metabolites are classified into three main groups, the flavonoids, the terpenoids and nitrogen-containing alkaloids and sulphur- containing compounds. Thousands of African plants and their derivatives have been screened for cancer treatment. A wide variety of secondary metabolites have been isolated from African plants that have been reported to be very active as anti-cancer agents. These include Benzophenones; Flavonoids; Pterocarpan; isoflavonoids; naphthoquinone; Acridone alkaloids and Xanthone. The plant derivatives have been reported to be effective in the treatment of both cancer and multi-drug resistant (MDR) cancer (Kuete and Efferth, 2015.

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Some of the derivatives have been demonstrated to be more effective than others and are already in clinical use as anticancer agents. These include the vinca alkaloids, vinblastine and vincristine, which were all originally isolated from the Madagascar periwinkle (Catharanthus roseus) (Gragg and Newman, 2009). Other examples of these metabolites that have been found to be cytotoxic to cancer cell lines include, paclitaxel from Taxus baccata, camptothecin from Camptotheca acuminate, monocrotaline from Crotolaria sessiliflora L.,

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and colchicine derived from Colchicum autumnale L.. There are also secondary metabolites extracted from African medicinal plants known to be cytotoxic to cells displaying Multi Drug

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Resistance (MDR), these are terpenoids, phenolics and alkaloids. The chemical structure of

lines.

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secondary metabolites determines its effectiveness in specifically acting against cancer cell Flavonoids contain hydroxyl (-OH) and methoxy (-OCH3) groups. It has been found

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that flavonoids with one hydroxyl and one methoxy groups have lower anti-proliferation effects as compared with one containing more than one group. This difference has been demonstrated in leukaemia and carcinoma cells (Kuete et al, 2014). The pholyphenylation

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and other substitutions in the cycle structure of phenolics also influence the anti-proliferation capacity of benzophenones (Kuete, 2013). This indicates that when selecting plant secondary

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metabolites it is important to also consider their chemical structure.

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Medicinal plants play a major role in primary health care in many developing countries. Scientific evidence has been reported in some of these plants although further research is required to confirm their efficacy and safety (Bungu et al, 2006). About 50% of modern

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drugs in clinical use are derived from natural products. Many of these compounds have the ability to induce apoptosis and control cancer cells (Madhuri and Pandey, 2009; Mthembu and Motadi, 2014). Even in developed countries such as the US many of the pharmaceutical prescriptions contain at least one plant derivative, making plants an important natural source of medicine (Mthembu and Motadi, 2014).

Despite this it has been reported that in

industrialized countries medicinal herbs had lost importance during the course of chemistry’s progression in the twentieth century but recently they have shown an impressive revival (Efferth et al, 2008). Medicinal plants can also be multi-functional being used to treat more than one disease. Table 1 shows one medicinal plant’s task in different functions.

ACCEPTED MANUSCRIPT Medicinal plants in Africa are mostly used by traditional healers to heal people orally or by being applied to wounds in order to treat many of the diseases that occur in African communities (Sawadogo et al., 2012; Semenya et al., 2012). African populations tend to use medicinal plants as their main source of medicinal treatment as they cannot afford Western medicines or are suspicious as to the effectiveness of Western medicine and believe that natural products work better than modern drugs. There is a list of medicinal plants that have been used in Africa to treat communicable and non-communicable diseases (Table1) but our

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focus will be based on anti-cancer medicinal plants, looking at the effects of these medicinal plants in different cancer cell lines and regulations of genes involved in the inhibition of

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apoptosis in the establishment of cancer (Kuete and Efferth, 2015). Table 1 below shows a

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list of medicinal plants that have been screened by researchers looking at traditional plant medicine cytotoxicity in cancer cell lines. Great achievements have been made in establishing

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the effect medicinal plants and their derivatives have on the regulation of gene expression. However, new technologies allow the extension of investigations into the effect these

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compounds have on other levels such as gene splice sites. 5. Medicinal plants methodology to investigate their effects in cancer cell lines

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In cancer studies, medicinal plants are screened through cell lines for each particular cancer. The mechanisms are achieved in four different stages of research: Cell culture; cell treatment,

5.1.

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Protein/ gene analysis. Figure 2 below summaries these methods step by step. Growing of cell lines/ cell treatment

These cells are grown, normally until they are 70-80% confluence and then passaged and

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grown in a particular growth medium where after 24 hours they are treated with dilutions of plant extracts. A cell proliferation assay is essential to determine if that particular plant extract has an effect on that particular cancer. It gives an IC 50 value; this value determines the concentration that is suitable to treat cancer cells. Kuete and Efferth have proposed the use of twice the IC50 to be effective against MDR cell lines (Kuete et al., 2014). 5.2.

Protein/ gene analysis

As the cells are treated with medicinal plant extracts, proteins and RNA are extracted for both gene and protein analysis. RNA is reverse transcribed to get cDNA, to allow for gene transcription analysis using conventional qPCR (Dlamini et al., 2016). In addition to gene

ACCEPTED MANUSCRIPT transcription levels the conventional PCR technique is required to indicate changes in gene splice sites.

6. Action of medicinal plants with cytotoxicity on cancer African medicinal plants studies have shown good anti-proliferation activities in both cancer

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cell lines and drug resistant cancer cell lines. The section is based on the following topics:

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proliferation, apoptosis, angiogenesis, invasion/metastasis, and adjuvant drugs.

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6.1 Proliferation

There are some mechanisms that are strictly regulate cell cycle that maintain tissue homeostasis. Failure in regulatory mechanisms may lead to uncontrolled cell proliferation

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leading to the development of tumours. There are two types of tumours, noncancerous (benign) or cancerous (malignant).

Benign do not accumulate the body parts although may

and

destroy

normal tissues.

The

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cause discomfort due to bleeding however; malignant tumours accumulate to other body parts accumulation

of malignant

tumours

(uncontrolled

proliferation) to attack other surrounding tissues and metastasize to other organs is known as

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cancer (De Stefani et al., 2005). There are some factors that are involved in cancer development and those involves age, carcinogens, genetic alterations and environmental

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factors. These factors may lead to genetic mutations that may inhibit the induction of apoptosis and changes in other regulatory mechanisms (Armes et al., 2005). African medicinal plants have been hypothesized and practically proved to change the expression of

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some proteins such as RBBP-6 protein expression. The expression change was due to Tulbaghia violacea treatment in cervical cancer cell lines. Tulbaghia violacea is a medicinal plant from Limpopo in South Africa (Mthembu and Motadi, 2014).

6.2 Apoptosis Apoptosis or programmed cell death is the process that is used to remove unwanted; old or injured cells (Safarzadeh et al, 2014). Apoptosis is initiated by either death receptors, which are using caspases 8 and 9 or mitochondrial pathways, which utilize caspase 9. Understanding

the

mechanisms underlying cancer development is important for the

development of treatment. Apoptosis induction in tumour cells is an attractive target for the

ACCEPTED MANUSCRIPT development of cancer treatment for the prevention of cancer. A wide range of natural products has been reported to induce apoptosis in different tumour cells (Mousavi et al, 2015). Mitochodrion are known to a role in the intrinsic apoptotic pathway. It play a role in the apoptotic response areas and non-receptor stimuli such as toxins, hypoxia, viral infections and lack of certain hormones and growth factors. These stimuli lead to a reduction in the mitochondrial membrane potential which is an indication of the irreversible process of early apoptosis due to an increase in the permeability of the mitochondrial membrane followed by

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the release of apoptotic factors, including cytochrome c. Intrinsic signalling pathways have been reported to be the main pathway that triggers apoptosis which is an active process for

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normal cells to counter-balance cell proliferation and apoptosis acts as a safeguard to

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eliminate any altered and harmful cells that may lead to cancer (Eberle and Hossini, 2008). In response to altered cellular conditions or cellular dysregulation that would result from the

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expression of oncogenes, cells initiate the intrinsic pro-apoptotic pathways. In this case mitochondrial pathways are highly active as they release mitochondrial pro-apoptotic cofactors into the cytoplasm. Figure 4 outline the steps that lead to apoptosis in Melanoma

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cells and how Bcl-2 proteins control mitochondrial pathways (Eberle and Hossini, 2008). The tumour suppressor protein p53 is kept at low levels in normal cells because of its short half-

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life and degradation by the proteasome pathway. In Mitochondria, in response to DNA damage or oncogene activation,

p53

is stabilized

by modification steps such as

phosphorylation by ataxia telangiectasia mutated (ATM), ATM and rad3-related (ATR) or

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checkpoint kinases. Through various steps p53 drives the expression of various proteins, which results in a cessation of cell division. The transcriptional factor p53 also triggers the transcription of pro-apoptotic factors in particular pro-apoptotic Bcl-2 proteins such as Bax,

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Noxa, Puma, Bik/Nbk and Bid. Furthermore to trigger mitochondrial apoptosis, p53 may also directly interact with Bcl-2 family members (Eberle and Hossini, 2008; Sethi et al., 2007). The function of Bcl-2 family members is to inhibit apoptosis in cancer cells (Eberle and Hossini, 2008). The Bcl-2 family of proteins must be the targets of African medicinal plants and it derivatives. Medicinal plants screening is required to identify compounds that can decrease the expression of Bcl2 and promotes the expression of Bax/Bak, which in turn will induce, cell death. It has been shown that African medicinal plants change protein expression involve in cancer by inducing apoptosis in mutated cancer cells (Mthembu and Motadi, 2014; Kuete et al., 2011). 6.2. Angiogenesis

ACCEPTED MANUSCRIPT New blood vessel formation in the body is part of the normal process in life and is termed angiogenesis. Angiogenesis also plays an important role in other diseases including cancer. Tumours require new blood vessel formation to supply nutrients and oxygen. This is achieved by sending signals to stimulate the growth of new blood vessels that will send blood to these tumours (McMahon, 2000). As a result the inhibition of apoptosis is an anti-cancer research target. The inhibition of angiogenesis pathways is an indirect way of targeting cell proliferation and tumour metastasis but so far there are no studies in my knowledge has

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shown inhibition of angiogenesis using African medicinal plants.

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6.4 Invasion and metastasis

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Metastasis of cancer is the accumulation of cancer cells to tissues and organs away from where the tumour originated and this accumulation of new tumours is the main results of

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death of most patients with cancer. This process contributes to cancer as a multiplex disease. Changes in cell to cell and cell to matrix adhesion are the vital ways of metastasis (Martin Jiang, 2009). Metastasis has three main processes: invasion, intravasation and

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and

extravasation. The dissociation of malignant tumours from primary tumour mass and alteration of cell to matrix allows the cells to invade the surrounding stroma and that process

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is called invasion. The process involves the secretion of chemicals that degrade the basement membrane and extracellular matrix (Brooks, 1996).

The movement of blood vesels within

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tumour areas provide a way for the detachment of cells to circulatory system and metastasize to other sites and this process is known as intravasation (Folkman and Shing, 1992 and Folkman, 1996). Intravasation is followed by the interaction between the tumour cells and the

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stroma in the development of angiogenesis (Ono et al., 1999). Then the development of adhesion to the endothelial cell sand penetrates the endothelium and the basement membrane occur and this process is called extravasation. The new settled tumour can then proliferate at the secondary location.

6.5 Adjuvant drugs There are many African medicinal plants that are known to induce apoptosis, since induction of apoptosis indicates the cytotoxicity of antitumor agents. Their action is to induce or reestablish apoptotic pathways that have been inhibited in cancer cells (Safarzadeh et al., 2014). These medicinal plants are screened in conjunction with normal cells and extracts that acts in cancer cells but not in normal cells are the one selected as good candidates to establish

ACCEPTED MANUSCRIPT anticancer drugs. The following African medicinal plants are reported to induce apoptosis and inhibit cell proliferation: Tulbaghia Vaolacea and Agave palmeri were reported to induce apoptosis in cervical cancer but not in normal cells and that indicated that this plant only inhibit cancer cells (Mthembu and Motadi, 2014). Echinops Giganteus; Imperata cylindrica and Piper Capense (Kuete et al., 2013) and Gladiolus Quartini-anus; Vepris soyauxii; Anonidium Mannii (Kuete et al., 2013), were found to induce apoptosis in multidrugresistant cancer. Six flavonoid compounds were extracted from the stem bark of E.

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addisoniae. Two of these compounds were found to be highly toxic to liver cancer cells by

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inducing apoptosis (Passreiter et al., 2015).

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Some plant natural products have been reported to induce apoptosis in neoplastic cells but not in normal cells. Apoptosis is a vital process for anti-tumour agents, ionizing radiation, and

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some of the alkylating agents such as cisplatin and 1-3-bis(2-chloroethyl)-1 nitrosourea, topoisomerase inhibitors etiposide, cytokine tumour necrosis factor (TNF), taxol, and Nsubstituted such as metoclopramide and 3-chloroprocainamide (Mthembu and Motadi, 2014).

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So screening apoptosis inducers is very important either in the form of plant extracts or

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secondary metabolites.

The induction of apoptosis in tumour cells is considered useful in the management, therapy as

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well as in the prevention of cancer. A wide variety of natural substances have been documented to have the ability to induce apoptosis in different tumour cells. In this regard, screening apoptotic inducers, either in the form of crude extracts or as components purified

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from these extracts, is very important. A good example of medicinal plants extract is Centratherul antihelminticum (L) (CACF). These plants extracts act by elevating the levels of oxidative stress by inducing ROS production (Looi et al., 2013). Figure 3 summarises the basic steps of apoptosis induction (Looi et al., 2013). Reactive oxygen species (ROS) are described as chemical reactive molecules, which contain oxygen, e.g. peroxides; superoxide; hydroxyl radical and singlet oxygen. In normal metabolism, ROS is formed as a natural product of oxygen and it plays a vital role in cell signalling and homeostasis. At times of oxidative stress e.g. ultra violet and/ or heat exposure that may results in cell structure damages, ROS levels are increased (Devasagayam et al., 2004). ROS- related oxidation of DNA could produce many types of DNA damage due to its potential to causing mutations (Waris and Ahsan, 2006). Although ROS functions is to mediate the induction of cell

ACCEPTED MANUSCRIPT proliferation in cancer cells, it has been reported that medicinal plants and derivatives that can inhibit ROS can also inhibit cell proliferation (Mthembu and Motadi, 2014; Ames, 1983). The medicinal plants from African countries require careful selections; since some studies reported that natural product such as coumarin (benzopyran-2-one or chromen-2-one) (Mousavi et al., 2015) are the most active inducers of apoptosis in cancer. Since African medicinal plants have different chemical structural compositions, their cytotoxicity in cancer

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cell lines will differ. Cancer mutations with high levels of angiogenesis can lead to pathogenic factors; therefore

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African compounds with anti-angiogenic properties may be very important in prevention,

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cancer treatment and other diseases (Carmeliet, 2003, Paper, 1998). There are also plants that are already reported to have an anti-angiogenesis effect such as plant extracts from Echinops giganteus, and Zingiber officinale, they are reported to inhibit angiogenesis in quail embryos

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(Kuete et al., 2011). It may be important to screen more African plants to combat angiogenesis and adjust protocols in order to account for cytotoxicity. Reports indicate that

platelet-derived

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researchers target angiogenic factors such as vascular endothelial growth factor (VEGF), growth factor (PDGF),

fibroblast growth factor (FGF), angiopoietin,

transforming growth factor beta-1 (TGF-β1), transforming growth factor alpha (TGF-α), and

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epidermal growth factor (EGF). VEGF factor is the most characterized protein of these factors because it acts directly to initiate angiogenesis. VEGF elicits a pronounced angiogenic

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response in a variety of in vivo models (McMahon, 2000). In therapeutic strategies researchers target VEGF pathways because VEGF and its receptors have been shown to connect in angiogenesis that occurs in many solid tumours and the formation of solid tumours

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is known to be angiogenesis dependent. Medicinal plants also target VEGF and its receptors in order to inhibit angiogenesis (Kurebayashi et al., 1999; Shaheen et al., 1999; Yoshiji et al., 1999). Since VEGF is reported as the key in the regulation of angiogenesis it is important to target this pathway to inhibit angiogenesis through its angiogenic factors. Figure 5 shows angiogenesis pathway that may lead to cancer disease and also indicates the sites of the pathway where plant extracts may be used as particular targets. In this pathway the plant extracts may inhibit the binding site for VEGF ligand or inhibit the phosphorylation in response to VEGF ligand binding so by doing that cell proliferation, cell migration and vascular permeability/ enhancement of cell survival will be inhibited and apoptosis will be favoured (Roviello et al., 2016).

ACCEPTED MANUSCRIPT When investigating the anticancer activity of aqueous extracts of Ximenia Americana it was demonstrated that the extract is differentially cytotoxic to a variety of cell types. This implies that the activity is selective. The fact that the extract was more active against higher cell densities indicates that this selectivity is based on cell proliferation rate, with the extracts being more toxic to cell with a higher proliferation rate. The active compound in this extract was identified as being a protein with galactose affinity. This protein has amino acid

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sequence identity with the ribosome inactivating protein ricin (Voss et al., 2006). 7. Anti-cancer compounds found in plants

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There are anti-cancer compounds that are found in medicinal plants which are reported to

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have some activity in cancer cell lines. Table 2 outline these compounds, cell lines that show effects after treatment and their mechanisms. This section also discusses below the

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mechanical structures of these compounds, medicinal plants these compounds found and their mechanical activities.

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7.1 Alkaloids

Alkaloids are a diverse group of secondary metabolites that are nitrogen-containing organic

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compounds with the exception of amino acids, peptides, purines and derivatives, amino sugars, and antibiotics. They can be classed as either, true alkaloids with a heterocyclic nitrogen atom or pseudo alkaloids. They have an array of structural types (figure 6) (Kuete The ability of small alkaloid compounds to inhibit angiogenesis is

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and Efferth, 2015).

demonstrated by the compound Vincristine which inhibits tubulin dimers from binding each other inhibiting microtubule formation (Khalid et al., 2016). Alkaloids have been shown to

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block the formation of microtubule and karyokinetic spindles, resulting in the inhibition of mitosis at metaphase, cell death, and the inhibition of angiogenesis. Leading to these compounds being identified as useful in the treatment of cancers (Khalid et al., 2016). Alkaloids are capable of inhibiting cancer cell growth have been isolated from African indigenous plants such as Jatropha curcas, Calotropis procera, Acacia macrostachya and Holarrhena floribunda (Sawadogo et al., 2012). Additionally, alkaloids that are cytotoxic to cancer cells have been isolated from African indigenous plant such as Echinops giganteus, Cajanus cajan, Balanites aegyptiaca and Acanthospermum hispidum (Sawadogo et al., 2012). Acridone alkaloids (helebelicine A, 3-hydroxy-1-methoxy-10-methyl-9-acridone, 1hydroxy-3-methoxy-10-methyl-9-acridone,

and

1-hydroxy-2,3-dimethoxy-10-methyl-9-

acridone) isolated from the fruits of Zanthoxylum leprieurii from in Cameroon, showed

ACCEPTED MANUSCRIPT moderate activity against human lung carcinoma cells A549 and colorectal adenocarcinoma cells DLD-1 (Kuete and Efferth, 2015). The acridone alkaloid arborinin (figure 6) that was isolated from the fruits of Uapaca togoensis was cytotoxic against multiple cancer cell lines. It was found to induce cell cycle arrest between the G0/G1 and S phase. Tropanes extracted from Erythroxylum restore drug sensitivity to MDR cancer cells (Mi et al., 2002).

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7.2. Phenols

Polyphenolic compounds are synthesised from phenylalanine or tyrosine. The have at Least

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one aromatic ring substituted with hydroxyl groups (figure 7). Polyphenols are strong

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antioxidants many of the phenolic compounds isolated from plants show cytotoxic effects against tumors. Curcumin is a phenolic yellow compound found in many plant species and is

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the basis for many spices and fragrances such as turmeric. This compound inhibits the formation of tumours by interfering with the growth, proliferation, angiogenesis and metastasis. However, it is not toxic to humans at relatively large doses (Safarzadeh et al.,

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2014). Ginger Zingiber officinale is also rich in phenol compounds that display cytotoxic activity against cancer cells. This activity is increased when these extracts are combined with

al., 2016).

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those from Curcuma longa (curcumin containing species) (Kurapati et al., 2012; Khalid et African plants such as Echinops giganteus and Dorstenia psilirus contain

phenolic and polyphenolic compounds that show significantly high cytotoxic activity against

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cancer cells (Sawadogo et al, 2012). Phenolic compounds from Detarium microcarpum inhibited the growth of MDA-MB 231 cells.

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Flavonoids are a large class of secondary metabolites, produced by plants for protection against photosynthetic stress, reactive oxygen species and wounds. Many flavonoids and their derivatives exhibit anti-cancer activities. Isoflavones are structurally similar but not derived from steroids (cholesterol). They include quercetin, luteolin, apigenin, kaempferol, and genistein (Figure 7). They exert pro-apoptotic effects by blocking proteasome activity and inhibiting angiogenesis (Khalid et al., 2016). Quercetin-3-O-glucoside isolated from South African Moringa oleifera showed significant cytotoxicty against epatocellular carcinoma and colon carcinoma cells and low cytotoxicity against normal embryonic kidney cells (Maiyo et al., 2016). Quercetin inhibits angiogenesis by blocking the EGF receptor and disrupting the NF-κB and HER-2 signalling pathways (Khalid et al., 2016). Prenylated flavones (containing hydrophobic residues) generally have the ability to inhibit NF-κB. The West African plant

ACCEPTED MANUSCRIPT Erythrina addisoniae contains prenylated flavones that were active against hepatoma cells, inducing cell death through apoptosis and at higher concentrations, necrosis (Passreiter et al., 2015). In terms of acting as anti-angiogenic compounds in the treatment of cancers flavonoids and chalcones regulate expression of VEGF, MMPs, and EGFR and inhibit NF-κB, PI3-K/Akt, and ERK1/2 signaling pathways (Khalid et al., 2016). One particular chalcone isolated from

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Polygonum limbatum, 4_-hydroxy-2_,6_-dimethoxychalcone, arrested the cell cycle between Go/G1 phase, strongly induced apoptosis via disrupted mitochondrial membrane potential

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(MMP) and increased production of reactive oxygen species (ROS) in the studied leukemia

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cell line (Kuete et al., 2014).

Terpenoids are derived

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7.3. Terpenes

from five-carbon isoprene units and include monoterpenes,

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sesquiterpenes, diterpenes, sesterterpenes, triterpenes and tetraterpenes. The anti-cancer activity of many African traditional plants is due to terpenes. The oleanane-type triterpenoid was obtained from the roots of the Madagascan plant Albizia gummifera and showed activity

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against A2780 human ovarian cancer cells (Mthembu and Motadi, 2014), while the diterpene Cafestrol from Coffea arabica inhibits angiogenesis (Moeenfard et al., 2016). Xanthorrhizol

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is a sesquiterpenoid terpeoid complex derived from rhizome of Curcuma xanthorrhizza. Studies in vivo have shown that Xanthorrhizol inhibits formation and development of tumors (Kang et al., 2009). It reduces protein expression of ornithine decarboxylase, cyclooxgenase-

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2 (cox-2) and suppresses NF-KB signalling activity. The reduction in cox-2 levels results in an anti-metastatic activity observed in in vivo mouse lung metastasis model. This is accompanied by matrix metallopeptidase 9 (MMP-9) activity (Safarzadeh et al., 2014). The compound is also active against colon cancer cells, where it down-regulates cell proliferation and increases apoptosis levels resulting in DNA fragmentation, cytochrome C release and caspase activation (Kang et al., 2009).

Targeting the angiogenic pathways is a promising target for the development of anticancer drugs. Ethanol extracts from Orthosiphon labiatus are active against breast (MCF-7) human cancer cell lines. The active compound is a diterpene carnosic acid and two labdane diterpenoids,

while similar compounds abietane diterpenoids carnosol, rosmadial, and

ACCEPTED MANUSCRIPT carnosic acid were extracted from Salvia Africana. These compounds were also cytotoxic against the (MCF-7) human cancer cell line (Hussin et al., 2007). Carnosic acid and carnosol are phenolic compounds that can also be found in the plant Rosmarinus officinalis. The compounds display antioxidant, anti-inflammatory, and cytotoxic properties Carnosic acid has the stronger antioxidant, antibacterial, and anti-obesity activity. It also inhibits platelet aggregation and is antiangiogenic (Khalid et al., 2016).

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Other terpenoids increase the anti-cancer activity of existing drugs. Extracts of Polyscias fulva contain alpha hederin (figure 8) a saponic Triterpenoid that enhances the cytotoxicity of

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other chemotherapy agents and causes an increase in the levels of Reactive oxygen species

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leading to increased apoptosis (Randhawa and Alghamdi, 2011). Another promising finding is that some terpenoids such galanals A and B (figure 8) as are isolated from the

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Cameroonian spice Aframomum arundinaceum selectively cytotoxic, killing some cells but leaving other cell lines unharmed (Kuete et al, 2011).

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8. African medicinal plants on their way of developing as anti-tumor drugs National Cancer Institute (NCI) launched a collection and screening programme of medicinal

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plants in 1960. This screening programme led to the isolation of new cancer drugs e.g. Taxanes and campothecins. Taxanes and campothecins have been identified as effectively

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killing a wide range of cancer cells. Taxol (paclitaxel) isolated in bark of Taxus brevifolia and is used in treatment of breast cancer, ovarian and lung cancer. Campothecin has active clinically active agents and isolated from Campotheca aciminate, Topotecan and Ironotecan

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(Saklani and Kutty, 2008). They are used in the treatment of colorectal, lung and ovarian cancers. Some publications also includes Homoharringtonine, which is a clinically active agent to treat leukemia and it is isolated from Cephalotaxus harringtonia (Chin et al., 2006) and Elliptinium from Bleekeria vitensis known to treat breast cancer (Shoeb, 2006; Cragg and Newman, 2005). Among African medicinal plants, Hypoxis hemerolloide; Aloe ferox; Aspalathus linearis; and Harpagophytum procumbens under investigation to develop antitumour drugs. The rhizome of Hypoxis hemerocalloide in South Africa is used in the treatment of urinal tract infection. It has been identified to contain a diglucoside compound known as

ACCEPTED MANUSCRIPT hypoxoside which produces the aglycone rooperol which is cytotoxic to certain cancer cells and is currently under clinical trials (Drewes, 2012). Aloe ferox is a plant found is South Africa and Lesotho. It is known as the most common Aloe species in South Africa’s wild harvested commencially traded species (Brendler et al., 2010; Merlin, 2009; Van Wyk and Gericke, 2000). Articles reported that A. ferox has a gel which has at least 130 medicinal agents with anticancer, antiviral, antitumor anti-

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inflammatory and analgesic effects which encompasses all of the traditional uses and scientific studies done on A. ferox and its constituents (Gurib-Fakim et al., 2010, Merlin,

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2009, Van Wyk et al., 1995). Chromones, anthraquinones, anthrone, anthrone-C-glycosides

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and other phenolic compounds have been found within A. ferox and they have been reported to possess biological activities (Van Wyk and Wink, 2004, Merlin, 2009, Van Wyk et al., 1995). According to reports, the leaf gel has been found to be rich in antioxidant polyphenols,

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indoles and alkaloids. The plant is still under investigation in cancer diseases, since only

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experiments done with no clinical reports published yet.

Aspalathus linearis (Rooibos) is a South African fynbos species which is cultivated in order to produce herbal tea known as rooibos. It has no caffeine with low tannin status and its

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potential health-promoting properties. It has a notable antioxidant activity that contributed to its popularity and consumer acceptance (Joubert and de Beer, 2011; Van Wyk et al., 2003;

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Van Wyk and Verdoorn, 1989; Kawano et al., 2009). Rooibos has been discovered as a refreshment drink and healthy tea beverage (Gurib-Fakim et al., 2010; Brendler et al., 2010). Through research,

animal studies suggested

that rooibos has a potent antioxidant,

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immunomodulating, and chemopreventive effects. Among flavonoids found in this plant, there are unique C-glucoside dihydrochalcones called aspalathin and nothofagin. Aspalathin has been reported as the most abundant one (Gurib-Fakim et al., 2010). Rooibos flavonoids has a growing evidence that it contributes a reduction in cardiovascular disease and ailments associated with ageing (Kawano et al., 2009). Two reported studies concerning inhibition of COX-2 in mouse skin (Na et al., 2004) and inhibition of mouse skin tumor promotion supported the role of the topical application of rooibos extract. However, some research would be required to investigate its potential in preventing skin cancer in humans (Na et al., 2004).

ACCEPTED MANUSCRIPT Harpagophytum procumbens is found in Transvaal of South Africa, Botswana and Namibia (Gurib-Fakim et al., 2010). It has an ancient history of multiple uses and is the most commercialized traditional medicines from Africa. The bulk of this plant are exported mainly to Europe where it is made into health products such as tablets, capsules and teas (Mncwangi et al., 2012). Among other diseases this plant is used traditionally in blood diseases, boils, childbirth difficulties, malaria and skin cancer. It is used clinically as an anti-inflamatory and analgesic in joint diseases (Brendler et al., 2010). Since all traditional medicines were used to

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treat many diseases this plant is also suggested to be screened for anticancer activities.

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Conclusions

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African traditional healers have a history of treating diseases with medicinal plants and through research even modern drugs are developed through utilization of medicinal plants.

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That makes African medicinal plants a key not only for the development of new anti-cancer treatments but as a potential source for drugs to treat all diseases and throughout this review it has been highlighted that although there have been some improvements in research areas of

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African plant extracts and their derivatives, more work is required in order to isolate useful compounds that can be used to develop anti-cancer drugs. In order to aid in the development

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of drugs it is important to collaborate with people who perform computer aided approaches in order to predict what derivatives are required for a target protein receptors. This will help streamline the process of screening compounds as these computer models can identify

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compounds of interest to be tested as well as helping to identify compounds of interest whose structure is already known. The use of African medicinal plants also requires that investors establish the cytotoxicity of these compounds. This review proposes that it will be important

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for researchers to understand cancer pathways in order to know what proteins to target. New technologies such as Next generation sequencing can be used to establish what effects these compounds have on these target genes, and whether these compounds are selecting the expression of protein isoforms arising from alternatively spliced isoforms. Finally it has been noted that the cytotoxicity depends on chemical structural arrangements of African medicinal plants compounds.

Conflict of interest Authors declared that there is no conflict of interest

ACCEPTED MANUSCRIPT Acknowledgements We would like to thank the South African Medical Research Council for funding this work. 9. References

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Waris G, Ahsan H. Reactive oxygen species: role in the development of cancer and various chronic conditions. Journal of carcinogenesis. 2006;5:14. Ames BN. Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Science (New York, NY). 1983;221(4617):1256-64. Eberle J, Hossini AM. Expression and function of bcl-2 proteins in melanoma. Current genomics. 2008;9(6):409-19. Sethi G, Ahn KS, Pandey MK, Aggarwal BB. Celastrol, a novel triterpene, potentiates TNFinduced apoptosis and suppresses invasion of tumor cells by inhibiting NF-kappaB-regulated gene products and TAK1-mediated NF-kappaB activation. Blood. 2007;109(7):2727-35. McMahon G. VEGF receptor signaling in tumor angiogenesis. The oncologist. 2000;5 Suppl 1:3-10. Carmeliet P. Angiogenesis in health and disease. Nature medicine. 2003;9(6):653-60. 63. Paper DH. Natural products as angiogenesis inhibitors. Planta medica. 1998;64(8):686-95. Kuete V, Krusche B, Youns M, Voukeng I, Fankam AG, Tankeo S, et al. Cytotoxicity of some Cameroonian spices and selected medicinal plant extracts. Journal of ethnopharmacology. 2011;134(3):803-12. Kurebayashi J, Otsuki T, Kunisue H, Mikami Y, Tanaka K, Yamamoto S, et al. Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Japanese journal of cancer research : Gann. 1999;90(9):977-81. Shaheen RM, Davis DW, Liu W, Zebrowski BK, Wilson MR, Bucana CD, et al. Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer research. 1999;59(21):5412-6. Yoshiji H, Kuriyama S, Hicklin DJ, Huber J, Yoshii J, Miyamoto Y, et al. KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells. Hepatology (Baltimore, Md). 1999;30(5):1179-86. Roviello G, Ravelli A, Polom K, Petrioli R, Marano L, Marrelli D, et al. Apatinib: A novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer. Cancer letters. 2016;372(2):187-91.

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Figures:

Figure 1: The number of compounds of biological interest isolated in each geographical region of Africa [16].

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Figure 2: Summary of selected anti-cancer methods drawn from information of cell culture methods published. Figure 3: Schematic diagram illustrating the mechanism of apoptosis induction by CACF plant extract in melanoma cell lines [55]. Figure 4: Schematic diagram showing how Bcl-2 proteins control mitochondrial pathway [59] Figure 5: VEGF pathway schematic diagram showing the events of the pathway that lead to cell proliferation, cell migration and vascular permeability/enhancement of cell survival. It also indicates two medicinal plants possible target [68].

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selective in their ability to kill cancer cells.

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Table:

Table1: African medicinal plants with cancer cytotoxicity

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Table 2: Mechanisms and chemical structures of African medicinal plants in cancer cell

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lines

ACCEPTED MANUSCRIPT Table1: African medicinal plants with cancer cytotoxicity Plant species/ area of Plant

Traditional use

Mode of action

collection

High cholesterol and diabetes mellitus,

Salvia africana, South Africa

Coughs, colds, bronchitis (Kamatou et al, 2008). Treatment of bronchitis and dysenteric conditions asthma, stomach-aches and rheumatism.

Xylopia aethiopica, Angola, Cameroon Sudan Orthosiphon labiatus

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Central Africa Anisophyllea dichostyla (DRC)

Immune and skin disorders, inflammatory, infectious, parasitic and viral diseases (Kuete et al, 2014). Immune and skin disorders, inflammatory, infectious, parasitic and viral diseases (Kuete et al, 2014).

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Beilschmiedia acuta Cameroon

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Polyscias fulva, Cameroon

West Africa Treat various disorders, such as nausea or arthritis pain (Al-Nahain et al, 2014).

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Zingiber officinale, Cameroon

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Vepris soyauxii, Cameroon

Uapaca togoensis Pax, Cameroon

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Moringa oleifera Lam, South Africa

Apoptotic potential role of extracts in cervical cancer cells. Activates the p53 pathway (Mthembu and Motadi, 2014). Extracts decreased the viability of Hela cells in a concentrationdependent manner (Jafarain et al, 2014). Cytotoxic (Hussein et al, 2007).

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Southern Africa Ailments, anticancer and androgenic

Anti-cancer drug (Kuete et al, 2013). Treat Diarrhoea, female sterility, cough and dysentery (Omachi et al, 2015).

Anonidium mannii, Gladiolus quartinianus, Vepris soyauxii Cameroon

Apoptosis in leukaemia cells by alteration/loss of MMP (Kuete et al, 2013). Cytotoxic active against a breast (MCF-7) human cancer cell line (Hussein et al, 2007).

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Tulbaghia violacea, South Africa

(Khallouki et al, 2007). Combinatorial cytotoxic effects on the PC-3M prostate cancer cell line (Kurapati et al, 2012). Induced apoptosis associated with increased ROS generation and MMP breakdown in CCRF-CEM (Kuete et al, 2014). Bark extract inhibited proliferation of CCRF-CEM cells induced cell cycle arrest between G0/G1 and S phases (Kuete et al, 2014). Cytotoxic to cancer cells. Also increased levels of ROS (Kuete et al, 2013). The crude extract of the fruits induced apoptosis in leukemia cells due to disruption of the mitochondrial membrane potential (Kuete et al, 2015). All three extracts induced apoptosis in luekemia cells by loss of MMP. A. mannii extracts enhanced production of ROS (Kuete et al, 2013).

Enantia chlorantha Oliv, Nigeria Aframomum melegueta,, Eremomastax speciosa and Moringa oleifera Lam. Sierra Leona, Nigeria

For haematopoietic and antidiarrhoeal herb.

All extracts caused a reduction in growth and proliferation, cell cycle arrest, increase of p53, p21WAF1/Cip1 and p27Kip1 protein levels and induction of differentiation in melanoma cells

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Used as motion sickness, dyspepsia and hyperemesis gravidarum (Mahady et al, 2003). dysentery, hepatitis, rheumatic disorders and pain, as well as swellings and cancer

Unknown

Enantia chlorantha Oliv, Nigeria and Cameroon

Treats jaundice, malaria, fever, infective hepatitis (Adebiyi and Abatan, 2013).

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Eremomastax speciosa Cassia alata, Eleusine indica, Carica papaya and Polyscias fulva Guinea, Nigeria, Cameroon and Ghana Aframomum pruinosum Aframomum melegueta Enantia chlorantha Eremomastax speciosa Hibiscus cannabinus L Moringa oleifera Mormodica charantia Pausinystalia johimbe Zingiber officinale Gagnep, Gabon Aframomum polyanthum, and Aframomum arundinaceum Cameroon

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Extracts from these traditional plants have antioxidant activity and induce cell cycle arrest and differentiation in B16F10 melanoma cells (Gismondi et al, 2013).

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Used as laxative and as antihelmintic (Kuete et al, 2014).

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East Africa Pain treatment, antiparasitic

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Ximenia americana

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Aframomum melegueta, Cassia alata, Eleusine indica, Eremomastax speciosa, Carica papaya and Polyscias fulva K. Schum, Ethiopia Hibiscus cannabinus L, Egypt

Ferula hermonis Egypt

Cytotoxic and anticancer activities against cholangiocarcinoma (Plengsuriyakarn et al, 2012). Induced apoptotic cell death (caspase-3/7 activation, nuclear fragmentation) in hepatoma cells and necrosis at high concentrations (Passreiter et al, 2015). Anti-Inflammatory activities of extracts (Sagnia et al, 2014).

North Africa Used in food, in herbal drinks, in hot and cold beverages and as herbal medicine (Da-Costa-Rocha et al, 2014).

Ext ract s showed anti-cancer activity towards multiple cancer cell lines (Kuete et al, 2014). Cytotoxic Extracts have toxic side effects (Adebiyi and Abatan, 2013). Cytotoxic effect against various immortalised cell lines. Toxicity seems dependant on the proliferation rate of the cells (Voss et al, 2006). Anti-Inflammatory Activities of Extracts from, (Sagnia et al, 2014).

Aqueous extract inhibits growth of MCF-7 Human Breast Cancer Cell Line (Khaghani et al, 2011). Cytotoxic effect towards breast cancer cell line MCF7 and moderate activities towards other cell lines (Kuete and Efferth, 2015).

ACCEPTED MANUSCRIPT Table 2: Mechanisms and chemical structures of African medicinal plants in cancer cell lines Cell line

Mechanisms

Reference

Alkaloids, flavonoids, terpenoids, saponins, tannins, steroids

Hella, PC12

High inhibition of cancer cells growth by hexane extract

(Aiyelaagbe et al.,

Calotropis procera

Cardenolides, flavonoids, saponins, tannins, alkaloids

High anti-proliferative effect on a panel of cancer cell lines

Acacia macrostachya

Di and triterpenes, saponins, tannins, anthraquinones, alkaloids Polyphenols, flavonoids, triterpenes, phenols, tannins, anthraquinones, alkaloids, anthocyans Steroids, cardiac glycosides, anthraquinones, saponins, flavonoids, alkaloids, tannins Cardiac glycosides, tannins, anthraquinons, saponins, triterpenes and steroidal glycosides, alkaloids, flavonoids Flavonoids, anthocyanosides, saponosides, tannins, triterpenes and steroids Alkaloids

Hs683, U373, HCT -15, LoVo, A549, HL-60, SF295, MDAMD-435 KB cells MiaPaCa2 CCRF-CEM CEM/ADR5000

High cytotoxicity against cells

MCF-and CORL23 cells

Significant cytotoxicity on cells

Acanthospermum hispidum

Zanthoxylum leprieurii Zingiber officinale

Dorstenia psilirus

Detarium microcarpum

Salvia Africana Rosmarinus officinalis Polyscias fulva

Alkaloids, glycosides, saponins, phenols, tannins, flavonoids, triterpenoids, steroids Polyphenol, phenol, flavonoids, saponins, triterpenes and glycosides Phenolics, flavonoids, saponins, triterpenes, steroids and glycosides Diterpenes, sesterterpenes, triterpenes and tetraterpenes Abietane diterpenoids carnosol, rosmadial, and carnosic acid Carnosic acid and carnosol saponic T riterpenoid

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Albizia gummifera

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Balanites aegyptiaca

Anti-proliferative effect again KB cells

A549, U373, PC-3, Bx-PC3, LoVo, MCF- 7

Cytotoxicity effect on a panel of cancer cell lines and strong antioxidant activity

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Cajanus cajan

2011 ; Uche FI, Aprioku, 2008; Igbinosa et al., 2009; Arekemase et al., 2011) Silva et al., 2010; Moustafa et al., 2010; Mainasara et al., 2011)

(Sawadogo et al., 2012) Kuete et al., 2011; Fankam et al., 2011; T ene et al., 2004) (Mohanty et al., 2011; Ashidi et al., 2010)

(Al Ashaal et al., 2010; Sarker et al., 2000; Ya’u et al., 2011)

A549; HT 29; MCF-7; RPMI; U251

T otal essential oil induce a high cytotoxicity effect on cells.

(Ahmed et al., 2012; Potchoo et al., 2008)

A549 and DLD1 CCRF-CEM, CEM/ADR5000

Has moderate activity on the cells

(Kuete and Efferth, 2015) (Kuete et al ., 2011; Maikai et al., 2008; Venkata et al., 2011)

MiaPaCa2; CCRF-CEM; CEM/ADR5000 MDA-MB 231 cells

Significant cytotoxicity

Kuete et al ., 2011; Ngueguim et al., 2007)

Inhibition of growth in cells

A2780

Inhibition of cell growth

(Ebi and Afieroho, 2011; Okolo et al., 2012) (Mthembu and Motadi, 2014)

MCF-7

Cytotoxic against the human cancer cell line

(Hussin et al., 2007)

CEM/ADR5000

antioxidant, anti-inflammatory, and cytotoxic properties enhances the cytotoxicity of other chemotherapy agents

(Khalid et al., 2016)

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Echinops giganteus

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Chemical structure

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Me dicinal plant name Jatropha curcas

CCRF-CEM

Significant cytotoxicity

(Randhawa and Alghamdi et al., 2011)

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Figure 1: The number of compounds of biological interest isolated in each geographical

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region of Africa (Ntie-Kang et al, 2013).

Figure 2: Summary of selected anti-cancer methods drawn from information of cell culture methods published.

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Figure 3: Schematic diagram illustrating the mechanism of apoptosis induction by

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CACF plant extract in melanoma cell lines (Looi et al, 2013).

Figure 4: Schematic diagram showing how Bcl-2 proteins control mitochondrial pathway (Eberle and Hossini, 2008).

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Figure 5: VEGF pathway schematic diagram showing the events of the pathway that lead to cell proliferation, cell migration and vascular permeability/enhancement of cell survival. It also indicates two medicinal plants possible target (Roviello et al, 2016).

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Alkaloids

J) Isoxazaole

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N) Purine M) Indole Eserine from the Calabar bean

Q) Benzylamine Capsaicin from chilli peppers

D) Piperidine Coniine from poison hemlock

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K) Quinazoline Vasicine from Justicia adhatoda,

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I) Oxazole Annuloline Lolium multiflorum

G) Indolizidine Swainsonine isolated from locoweed it is a potential chemotherapy drug

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F) Quinolizidine Lupinine from Lupinus species

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E) Pyrrolizidine Retronecine from plants in the genera Senecio and Crotalaria

C) Tropane Atropine from the nightshade family and Cocaine

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B) Pyridine Trigonelline from Trigonella foenumgraecum

A) Pyrrolidine Cuscohygrine from coca

O) β-Phenylethylamine Mescaline in the peyote cactus (Lophophora williamsii

H Isoquinoline Morphines

L) Quinoline Quinine

P) Colchicine Colchicine

R) Abornin S) Pancratistatin

T) Narciclasine

Figure 6: Alkaloid Compounds from plants: (A-Q) Different families of alkaloid compounds found in plants. (R) Arborinin from Uapaca togoensis is cytotoxic against multiple cancer cell lines.

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Phenols

B ) Flavone

D) Luteolin

C) Kaempferol

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A) Flavonol Quercetin

F) Apigenin

H) Cafestrol

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G) Chalcone

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E) Curcumin

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Figure 7: Anticancer phenolic compounds from plants:

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Terpenes

A) Isoprene

E) Carnosol

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B) Alpha-hederin

C) galanal A

D) galanal B

G) Xanthorrhizol

F) Oleanane

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Figure 8 Terpenoids from plants: (A) Isoprene the basic building block of all terpenoids. (B) Alpha hederin increases the effectiveness of other chemotherapy drugs. (C and D) are selective in their ability to kill cancer cells.