Potential of Central, Eastern and Western Africa Medicinal Plants for Cancer Therapy: Spotlight on Resistant Cells and Molecular Targets

Cancer remains a major health hurdle worldwide and has moved from the third leading cause of death in the year 1990 to second place after cardiovascular disease since 2013. Chemotherapy is one of the most widely used treatment modes; however, its efficiency is limited due to the resistance of cancer cells to cytotoxic agents. The present overview deals with the potential of the flora of Central, Eastern and Western African (CEWA) regions as resource for anticancer drug discovery. It also reviews the molecular targets of phytochemicals of these plants such as ABC transporters, namely P-glycoprotein (P-gp), multi drug-resistance-related proteins (MRPs), breast cancer resistance protein (BCRP, ABCG2) as well as the epidermal growth factor receptor (EGFR/ErbB-1/HER1), human tumor suppressor protein p53, caspases, mitochondria, angiogenesis, and components of MAP kinase signaling pathways. Plants with the ability to preferentially kills resistant cancer cells were also reported. Data compiled in the present document were retrieved from scientific websites such as PubMed, Scopus, Sciencedirect, Web-of-Science, and Scholar Google. In summary, plant extracts from CEWA and isolated compounds thereof exert cytotoxic effects by several modes of action including caspases activation, alteration of mitochondrial membrane potential (MMP), induction of reactive oxygen species (ROS) in cancer cells and inhibition of angiogenesis. Ten strongest cytotoxic plants from CEWA recorded following in vitro screening assays are: Beilschmiedia acuta Kosterm, Echinops giganteus var. lelyi (C. D. Adams) A. Rich., Erythrina sigmoidea Hua (Fabaceae), Imperata cylindrical Beauv. var. koenigii Durand et Schinz, Nauclea pobeguinii (Pobég. ex Pellegr.) Merr. ex E.M.A., Piper capense L.f., Polyscias fulva (Hiern) Harms., Uapaca togoensis Pax., Vepris soyauxii Engl. and Xylopia aethiopica (Dunal) A. Rich. Prominent antiproliferative compounds include: isoquinoline alkaloid isotetrandrine (51), two benzophenones: guttiferone E (26) and isoxanthochymol (30), the isoflavonoid 6α-hydroxyphaseollidin (9), the naphthyl butenone guieranone A (25), two naphthoquinones: 2-acetylfuro-1,4-naphthoquinone (4) and plumbagin (37) and xanthone V1 (46). However, only few research activities in the African continent focus on cytotoxic drug discovery from botanicals. The present review is expected to stimulate further scientific efforts to better valorize the African flora.


INTRODUCTION
Cancer is a term for a series of malign diseases characterized by abnormal cell proliferation, leading to invasion and metastasis, the ultimate causes of deaths by cancer. The burden of neoplastic diseases affects the entire world population. Over the past two decades, there has been a slight improvement in cancer statistics due to diagnostic and therapeutic progresses and a better understanding of tumor biology (Siegel et al., 2014). However, cancer remains associated with very high mortality rates, which indicate still existing difficulties of effective treatment. Chemotherapy is one of the most widely used modes of anti-cancer therapy. However, the development of resistance of cancer cells to cytotoxic agents represents a main factor, which is responsible for the non-satisfactory treatment outcomes associated with malignant diseases (Singh and Settleman, 2010). In fact, most types of cancer cells reveal variable degrees of resistance to antineoplastic agents (Luqmani, 2005). In 2008, men in Africa had more than double of the rate of world liver cancer cases, whilst women had the highest incidence of cervical cancer of the world. Medicinal plants have long been used to fight against cancer. Several natural products isolated from medicinal plants including: terpenoids, phenolics, and alkaloids play an important role in cancer treatment (Kaur et al., 2011). More than 3,000 plants worldwide have been reported to exert cytotoxicity toward cancer cells (Graham et al., 2000;Solowey et al., 2014). About 80% of the rural African population almost exclusively uses traditional medicine for its primary health care needs (Farnsworth et al., 1985). For cultural and economic reasons, medicinal plants constitute the major part of traditional medicine. In the recent years, numerous African medicinal plants have been screened for their cytotoxic potential. This review deals with plants and derived molecules from Central, Eastern and Western Africa (CEWA) as potential resource for cancer chemotherapy with emphasis on their molecular targets. Countries of Central Africa include: Cameroon, Gabon, Equatorial Guinea, Central African Republic, Congo, Democratic Republic of Congo, São Tomé and Príncipe, Chad, Angola. East Africa comprises of Kenya, Uganda, Tanzania, Rwanda, Burundi, Sudan, Eritrea, Djibouti, Ethiopia, Somalia, Seychelles, Comoros, Mauritius Island, Madacascar, Mozambique, and Malawi. Western African countries include Benin, Burkina Faso, Ivory Coast, Gambia, Ghana, Guinea, Guinea-Bissau, Cape Verde, Nigeria, Mali, Mauritania, Niger, Liberia, Senegal, Sierra Leone, and Togo. Hence, the medicinal plants of CEWA described in the present review cover a considerable portion of the African continent.

OVERVIEW OF CANCER BURDENIN AFRICA
Cancer moved from the third leading cause of death worldwide in 1990 to the second leading cause of death after cardiovascular disease since 2013, with more than 8 million deaths in 2013 (Murray and Lopez, 1997;Lozano et al., 2012). Although significant progress has been made in recent years in cancer prevention and treatment (Edwards et al., 2014;Allemani et al., 2015), the burden of cancer is increasing as a result of a growing and aging population worldwide, in addition to risk factors such as smoking, obesity and diet. To adequately allocate resources for prevention, screening, diagnosis, treatment and palliative care, and to monitor its effectiveness, there is an urgent need for timely information on the burden of cancer for each country. It is worth noting that in several African countries, the cancer burden still remains unclear in terms of reliable epidemiological data, though most practicing physicians recognize that the number of cases among patients visiting local health facilities continuously increases (Omosa et al., 2015). By 2020, 15 million new cancer cases are annually expected, 70% of which will be from developing countries. African countries will account for more than a million new cancer cases per year and have to cope with them despite few cancer care services (Vorobiof and Abratt, 2007). In Africa, about a third of cancer deaths are potentially preventable. In sub-Saharan Africa in 2002, more than half a million deaths from cancer were reported, with nearly 40% related to chronic infections and smoking (Vorobiof and Abratt, 2007). Due to the lack of basic resources and infrastructure, most Africans, including those in CEWA, do not have access to cancer screening, early diagnosis, appropriate treatment or palliative care. For example, radiotherapy is available in only 21 of the 53 African countries, reaching less than 5% of the population, and consequently patients are deprived of life-saving treatment (Vorobiof and Abratt, 2007).

ABC Transporters and Drug Resistance
The adenosine triphosphate (ATP)-binding cassette (ABC) proteins are amongst the largest protein families found in all living organisms from microbes to humans (Efferth and Volm, 2017). The roles of ABC transporters include binding to and hydrolysis of ATP to fuel energy-dependent efflux of specific compounds across the membrane or to return them from the inner to the outer surface of membranes (Dean, 2009). Malignant cells resist to anticancer drugs by mutation or overexpression of drug targets, as well as by inactivation or efflux of the compounds to prevent cytotoxic drug concentrations sufficient to kill tumor cells (Gottesman et al., 2006). Human ABC transporters involved in drug resistance include ABCA3 or ABC3/ABCC (ABCA family), ABCB1 or MDR1/P-glycoprotein (P-gp) (ABCB family), ABCC1 or MRP1 and ABCC3 or MRP3/cMOAT-2 (ABCC family), ABCG2 or ABCP/MXR/BCRP (ABCG family) (Glavinas et al., 2004). The roles of P-gp, multidrug-resistance-proteins (MRPs) and breast cancer resistance protein (BCRP) in cancer drug resistance have been intensively investigated (Efferth, 2001;Gillet et al., 2007).

P-glycoprotein (P-gp)
P-gp is encoded by the ABCB1/MDR1 gene and was identified as the first ABC transporter to be overexpressed in multidrug resistant cancer cell lines (Kartner et al., 1985). P-gptransports and/or secretes substrates in normal tissues such as the kidney, liver, colon, and adrenal gland as well as in the blood-brain, blood-placenta, and blood-testis barriers to protect these tissues from harmful compounds (Katayama et al., 2014). P-gp is involved in the efflux of doxorubicin, daunorubicin, vincristine, etoposide, colchicine, camptothecins and methotrexate, leading to resistance of cancer cells to these molecules (Dean, 2009). Clinical trials with synthetic drugs undertaken since 1994 have not resulted in significant progress in the discovery of new blockbusters for chemotherapy (Dean et al., 2005). Combating cancer-drug-resistance with phytochemicals inhibiting ABCB1 could therefore be a more promising strategy to overcome multidrug resistance (MDR). Additionally, other ABC transporters such as ABCC1/MRP1 (Cole et al., 1992) and ABCG2 (Kim et al., 2002) are also overexpressed in cancer cells and could be targeted by plant products.

Breast Cancer Resistance Protein (BCRP, ABCG2)
MXR alias BCRP is an ABC transporter that plays a role in absorption, distribution, metabolism and excretion in normal tissues (Natarajan et al., 2012). Its overexpression in tumor cells confers resistance to chemotherapy by active extrusion of cytotoxic compounds. BCRP is involved in the efflux of mitoxantrone, topotecan, doxorubicin, daunorubicin, irinotecan, imatinib, and methotrexate (Dean, 2009). This receptor protein is involved in MDR of several tumor types including: acute leukemia and other hematological malignancies, head and neck carcinoma, breast cancer, lung cancer, brain tumors, hepatocellular carcinoma, gastrointestinal cancers such as pancreatic, colon, gastric and esophageal carcinomas (Natarajan et al., 2012).

Epidermal Growth Factor Receptor (EGFR/ErbB-1/HER1)
The epidermal growth factor receptor (EGFR; ErbB-1; HER1), a signal transducer for cell growth and differentiation, is the cell-surface receptor belonging to the ErbB family of receptors. This family consists of four closely related receptor tyrosine kinases, namely EGFR/HER1/ErbB-1, HER2/c-neu/ErbB-2, HER3/ErbB-3, and HER4/ErbB-4. Mutations affecting the activity or expression of EGFR can contribute to carcinogenesis (Zhang et al., 2007). Upon stimulation by ligands, EGFR is activated through homodimerization or heterodimerization and transmit signals to downstream substrates such as PI3K/AKT, RAS/RAF/MAPK, and STAT3/5 pathways, leading to cell proliferation and cell survival (Ji, 2010). Downstream substrates of EGFR have been found responsible for drug resistance meanwhile activation of PI3K/AKT pathway is essential for cancer cell survival (Ji, 2010). ErbB family receptors represent important targets of anticancer therapeutics such as tyrosine kinase inhibitors (TKIs; for example gefitinib and erlotinib) (Zhang et al., 2007).

Human Tumor Suppressor Protein p53
The tumor suppressor protein p53 is encoded by the TP53 gene in human beings and Trp53 gene in mice. It is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor (Surget et al., 2013). The gene p53 is involved in the regulation of cell fate in response to different stresses in normal cells through the differential regulation of gene expression. Abnormal p53 expression actively contributes to cancer formation and progression in malignant cells. The gene p53 is also associated with response to cancer treatment by regulating apoptosis, genomic stability, and angiogenesis. Overexpression of mutated p53 with reduced or abolished function is often associated with resistance to various cytotoxic drug such as cisplatin, temozolomide, doxorubicin, gemcitabine, tamoxifen, and cetuximab (Hientz et al., 2017).

Caspases as Anticancer Drug Target
Caspases or cysteine-aspartic proteases are a family of protease enzymes essential for programmed cell death and inflammation. There are 14 mammalian caspases, 12 of which are of human origin (caspases 1-10, 12, and 14). They can be classified into three main types, that are initiator caspase (2, 8, 9, and 10), executioner or effector caspases (3, 6, and 7) and inflammatory caspases (1, 4, 5, 11, and 12) (Galluzzi et al., 2016). Caspase-14 plays a role in epithelial cell keratinocyte differentiation, and forms an epidermal barrier that protects against dehydration and UVB radiation (Denecker et al., 2008). Upon activation, caspases cleave a variety of substrates including: proteins involved in signal transduction (apoptosis regulators, cytokines, serine/threonine kinases), structural proteins (cytoskeletal and nuclear) and proteins involved in regulation of transcription, translation and RNA editing (Howley and Fearnhead, 2008). Deregulation of caspase activation or expression also leads to neurodegenerative and autoinflammatory disorders (Howley and Fearnhead, 2008). Initiator caspase-9 is activated in the apoptosome, while caspase-2 is activated in the PIDDosome and caspase-8 or -10 in the death-inducing signaling complex (DISC) (Howley and Fearnhead, 2008). Activated initiator caspases activate effector caspases, which in turn cleave structural and regulatory proteins culminating in the features of apoptosis. The search for caspase modulators is a novel attractive therapeutic approach in cancer research (Howley and Fearnhead, 2008).

Mitochondria as Anticancer Drug Target
Mitochondria play a central role in cellular metabolism, calcium homeostasis, redox signaling, and cell fate as main ATP source. During ATP biosynthesis, reactive oxygen species (ROS) are generated. In many cancer cells, mitochondria appear to be dysfunctional (due to a variety of factors, such as oncogenic signals and mitochondrial DNA mutations), with a shift in energy metabolism from oxidative phosphorylation to active glycolysis and an increase in the generation of ROS (Wen et al., 2013).The energy metabolism is different between normal and cancer cells, providing a scientific basis for development of strategies to selectively target malignant cells. As a result of mitochondrial dysfunction, cancer cells rely more on the glycolytic pathway in the cytosol to generate ATP. Key enzymes in this pathway such as hexokinase II, glyceraldehyde 3-phosphate dehydrogenase (overexpressed in malignant cells) therefore became potential therapeutic targets (Wen et al., 2013). Mitochondria-targeting compounds can kill drug-resistant cancer cells due to their ability to initiate mitochondrial outer membrane permeabilization in mitochondria, independently of other upstream signaling processes that may be impaired in cancer cells (Fulda and Kroemer, 2011). Some potential therapeutic targets associated with mitochondria include NADPH oxidases (NOX), the translocator protein (TSPO), the mitochondrial protein known as complement component 1, q subcomponent-binding protein (C1qBP) and the monocarboxylate transporters (MCTs) (Wen et al., 2013). Compounds known to target the mitochondrial membrane potential are for instance the natural alkaloid pancratistatin, rhodamine-123, 4-phenyl-2,7-di(piperazin-1-yl)-1,8-naphthyridine, 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone and edelfosine (Wen et al., 2013). Natural products such ascurcumin, resveratrol, berberine and cerulenin target mitochondrial apoptotic pathway (Wen et al., 2013).

Reactive Oxygen Species and Cancer Chemotherapy
Reactive oxygen species are chemically reactive chemical species containing oxygen such as hydroxyl radical, peroxides, superoxide, and singlet oxygen. They are produced through multiple mechanisms depending on cell and tissue types by NOX complexes in cell membranes, mitochondria, peroxisomes and endoplasmic reticulum (Muller, 2000;Han et al., 2001). ROS not only induce apoptosis, but also regulate host defense genes or airway homeostasis (Conner et al., 2002;Rada and Leto, 2008). In malignant cells, ROS induce changes in cellular functions such as cell death, cell proliferation, migration and differentiation (Wen et al., 2013). Increased ROS levels and mitochondrial dysfunction make cancer cells more vulnerable than normal cells.

Angiogenesis as Anticancer Drug Target
Angiogenesis is a physiological process in embryogenesis, in wound healing and in the female reproductive cycle leading to the formation of new blood vessels from pre-existing ones (Kumaran et al., 2008;Birbrair et al., 2015). Angiogenesis is critical in cancer for growth and metastasis, as tumors cannot grow beyond 200-300 µm in diameter without recruitment of new blood vessels to maintain nutrients and oxygen supply (Kumaran et al., 2008). This also makes angiogenesis an ideal target for cancer treatment. Some established therapeutic strategies targeting angiogenesis include bevacizumab [antibody to vascular endothelial growth factor (VEGF)], sorafenib and sunitinib (tyrosine kinase inhibitors). Combretastatin (vascular disruptive agents) and endostatin (endogenous inhibitor) are currently in clinical trials (Kumaran et al., 2008).

MAP Kinase Signaling Pathways in Cancer Chemotherapy
The mitogen-activated protein kinases/extracellular signalregulated kinases (MAPK/ERK) pathway or Ras-Raf-MEK-ERK pathway is one of the most important signal transduction pathways. The MAPK/ERK pathway regulates growth, proliferation, differentiation and survival of the cells. Its deregulation is observed in various diseases such as cancer, degenerative syndromes, immunological and inflammatory diseases, making it an important drug target (Orton et al., 2005). The activation of a MAPK employs a core three-kinase cascade consisting of a MAPK kinase kinase (MAP3K or MAPKKK), which phosphorylates/activates another MAPK kinase (MAP2K, MEK, or MKK), which in turn phosphorylates and activates more MAPKs. Upon activation, MAPKs can phosphorylate a variety of intracellular targets such as cytoskeletal elements, nuclear pore proteins, membrane transporters, transcription factors, and other protein kinases (Avruch et al., 2001). Mutations in proteins of this pathway, for example in Ras and B-Raf lead to carcinogenesis. Compounds targeting MAPK pathways are therefore investigated as potential cancer drugs (Orton et al., 2005). In fact, the role of stress-activated pathways such as Jun N-terminal kinase and p38 in the prevention of malignant transformation has been shown (Dhillon et al., 2007).

CENTRAL, EASTERN AND WESTERN AFRICA PLANTS AND DERIVED MOLECULES AND THEIR ANTICANCER TARGETS
During the past decade, intensive investigations of African medicinal plants as potential anticancer drug candidates have been carried out by African scientists in collaboration with various research teams throughout the world. However, this work should be strenghtened with particular emphasis on the study of mechanisms of action and the identification of the different molecular targets of bioactive substances. Here, we give an overview of the studies published so far on plants and products derived from CEWA as far as their molecular target are available. A synopsis of phytochemicals acting preferentially on cancer cell lines actively expressing drug targets such ABC transporters, EGFR, p53 and BCRP (Figures 1-3) will also be given. For instance the degree of resistance (DR) determined as the ratio of IC 50 value of the resistant/IC 50 sensitive cell line will be taken into account to consider samples with potential therapeutic values to combat MDR phenotypes. Hence, samples with hypersensitivity or collateral sensitivity (more active on resistant than on parental sensitive cells line with DRs below 0.90 as well as samples with regular sensitivity (DR between 0.91 and 1.19) will be discussed. According to the criteria of the American National Cancer Institute, 20 µg/mL is the upper IC 50 limit to be considered as promising for cytotoxic crude extracts (Suffness and Pezzuto, 1990). Meanwhile, a threshold of 4 µg/ml or 10 µM (Boik, 2001;Brahemi et al., 2010) after 48-72 h incubation has been set to identify compounds with considerable cytotoxic activity.

Plants and Derived Compounds Targeting the Mitochondria of Cancer Cells
Several crude extracts and isolated compounds from CEWA plants targeted mitochondria to induce apoptosis in cancer cells (Tables 1, 2).

African Plants and Compounds with Regular Sensitivity and Collateral Sensitivity in Drug Resistant Cancer Cells
The investigation of the mode of action of botanicals and phytochemicals from the flora of Africa is not yet done in a systematic manner due to the lack of facilities and appropriate technology in research centers throughout the continent. However, the fight against MDR in cancer will provide conceptual clues on the molecular targets of the active samples. In collaborations with more equiped research institutes in Western countries, plants and isolated compounds from the flora of CEWA were tested on cancer cells expressing well-known drug resistance phenotypes. In Tables 1, 2, results on samples are documented, that inhibited resistant cell lines with similar efficacy than sensitive ones (regular sensitivity). In some cases, it was observed that resistant cells were killed with even better efficacy than sensitive cells (hyper-sensitivity or collateral sensitivity). These plant extracts and phytochemicals could be especially useful to fight MDR in cancer. In this section, we will focus on plants and compounds exerting hypersensitivity on cell lines overexpressing ABC transporters, EGFR and with p53 knock out genes.

Plants and Compounds Acting in EGFR Over-Expressing Cancer Cells
Several plants extracts and compounds were more active in the resistant gliobastoma U87MG. EGFR cells than in its normal counterpart U87MG cells (D.R. < 0.90  . The methanol extracts of leaves and roots of the plant were tested on a panel of cancer cell lines, including MDR phenotypes. Both leaves and roots extracts displayed good antiproliferative effects with respective IC 50 values of 8.22 and 14.72 µg/mL in leukemia CCRF-CEM cells, 19.76 and 26.74 µg/mL in its resistant subline CEM/ADR5000 cells, 6.45 and 6.66 µg/mL in breast adenocarcinoma MDA-MB-231 cells and 21.09 and 22.75 µg/mL in its resistant counterparts MDA-MB-231/BCRP, 21.12 and 11.62 µg/mL in colon adenocarcinoma HCT116 p53 +/+ and its resistant counterparts HCT116 p53 −/− , 7.46 and 7.27 µg/mL in gliobastoma U87MG cells and its resistant counterparts U87MG. EGFR cells and 23.09 µg/mL for leaves extract in HepG2 cells . Interestingly, the two extracts were less toxic toward normal AML12 hepatocytes with IC 50 values above 40 µg/mL . Both leaves and roots extracts induced apoptosis in CCRF-CEM cells. However, the mode of induction of apoptosis was not dectected when MMP and ROS production were investigated .

Piper capense L.f. (Piperaceae)
Piper capense is a rather variable spicy plant ranging from a weakly erect, aromatic, evergreen shrub or subshrub, to a more or less herbaceous perennial and sometimes a straggling plant that scrambles into other plants for support. Piper capense is found from Guinea to Ethiopia, Angola and Mozambique. Traditionally, the plant is used as sleep inducing remedy, anthelmintic and to treat cancer (Kokowaro, 1976;Van Wyk and Gericke, 2000;Kuete et al., 2011a). The cytotoxicity of seeds methanol extract was reported toward CCRF-CEM cells (IC 50 : 7.03 µg/mL), CEM/ADR5000 (IC 50 : 6.56 µg/mL) and MiaPaca-2 cells (IC 50 : 8.92 µg/mL) (Kuete et al., 2011a)  . This extract was less toxic toward normal AML12 hepatocytes and HUVEC cells inducing less than 50% cell proliferation at 40 µg/mL and 80 µg/mL respectively (Kuete et al., 2011a. This extract induced apoptosis in CCRF-CEM cells by the loss of MMP and increase ROS production .

Polyscias fulva (Hiern) Harms. (Araliaceae)
Polyscias fulva is a deciduous to evergreen tree of the family Araliaceae. The plant is found in Tropical Africa, from Sierra Leone to Sudan, Ethiopia, and Yemen; in Angola, Zambia, Zimbabwe, and Mozambique. Traditionally, Polyscias fulva is used to treat malaria, fever, mental illness (Tshibangu et al., 2002), venereal infections and obesity (Jeruto et al., 2007;Focho et al., 2009), and cancer . The phytochemical investigations of the plant led to the isolation of polysciasoside A, kalopanax-saponin B, α-hederin (Bedir et al., 2001;Kuete and Efferth, 2011). Investigation of the cytotoxic potential of various parts of the plant demonstrated that the roots were more active than the leaves and bark   . Lower cytotoxicity of this extract was shown in normal AML12 hepatocytes with less than 50% cells proliferation at 40 µg/mL . The active constituent of the plant was reported as α-hederin and this compound had moderate antiproliferative effects (IC 50 values ranged from 7.43 µM in CCRF-CEM cells to 43.98 µM in U87MG. EGFR cells) against the above cancer cell lines . The roots methanol extract of Polyscias fulva induced apoptosis in CCRF-CEM cells, mediated by MMP alterations and increased ROS production .

HIT CYTOTOXIC COMPOUNDS FROM PLANTS OF CENTRAL, EASTERN AND WESTERN AFRICA
Several bioactive consituents of African medicinal plants were identified. They include: terpenoids, phenolics and alkaloids ( Table 2). However, phenolics were the best cytotoxic ingredients isolated from CEWA plants. In this section, a summary of the prominent antiproliferative phytochemicals identified in CEWA plant will be given.

Alkaloids
The isoquinoline alkaloid, isotetrandrine (51) (Kuete et al., 2015g). Alkaloid, 51 was less toxic against the normal AML12 hepatocytes, inducing less than 50% proliferation at up to 64.27 µM (Kuete et al., 2015g). This compound did not alter the integrity of the mitochondrial membrane in CCRF-CEM cells, and its mode of induction of apoptosis was mainly by increased ROS production (Kuete et al., 2015g).

Phenolic Compounds
Phenolics have been so far the most represented group of secondary metabolites isolated from CEWA medicinal plants. Several compounds with interesting cytotoxic activities were identified within benzophenones, flavonoids and isoflavonoids, naphthyl butenone, quinones and xanthones.

CONCLUSION
The present review paper aimed at compiling and summarizing relevant data on the potential of medicinal plant and isolated natural products from Central, Eastern and Western Africa to combat cancer with emphasis on their possible cellular targets. This report could not deliver medical results on the therapeutic capacities of the flora of these three African Regions as anticancer drugs. Nonetheless, in phytochemical and pharmacological basic sciences it clearly shows that efforts are being made by African scientists and their international collaborators to achieve this goal in the future. However, few research teams in the continent are already involved in the cytotoxic drug discovery from botanicals and it is expected that this review will stimulate other laboratories to undertake similar research projects to better valorize the African flora.

AUTHOR CONTRIBUTIONS
AM and VK wrote the manuscript; VK and TE designed and corrected the work. All authors read and approved the final version.