Anticancer activity of Nigerian medicinal plants: a review

Cancer is currently the leading cause of death globally and the number of deaths from cancer is on the rise daily. Medicinal plants have been in continuous use over the years for the management of cancer, particularly, in most developing countries of the world including Nigeria. The use of synthetic drugs for the treatment of cancer is often accompanied by toxic side effects. Thus, the alternative use of readily available and inexpensive medicinal plants is the panacea to the toxic side effects associated with synthetic drugs. The present review summarized the anticancer activity of 51 medicinal plants that are widespread in all regions of Nigeria. Furthermore, the proposed anticancer pharmacological actions as well as the anticancer bioactive compounds, the type of cancer cell inhibited, the plant parts responsible for the anticancer activity, and the nature of the extracts used for the studies were discussed in this review. The 51 Nigerian medicinal plants were reported to exhibit anticancer activities of the prostate, cervices, lung, skin, colon, esophagus, blood, ovary, central nervous system/brain, breast, stomach, pancreas, larynx, and kidney. The major classes of bioactive compounds indicated to be responsible for the anticancer activity include the polyphenols, flavonoids, alkaloids, saponins, triterpenes, tannins, and quinones. The major anticancer pharmacological actions of these bioactive compounds were antiproliferative, cytotoxic, cytostatic, antimetastatic, apoptotic, and antioxidative as well as provoked cell cycle arrest, inhibition of angiogenesis and reduction of cancer cell viability. The Nigerian medicinal plants can be harnessed to provide for readily available and inexpensive anticancer drugs in the future because the plants reported in this review showed promising anticancer activity.


Background
Cancer is currently the leading cause of death globally [1] and the number of deaths from cancer is on the rise daily. The number of recorded deaths of persons as a result of cancer rose by 17% between 2005 and 2015, and therefore, there is the urgent need for more intensive research into the development of new anticancer drugs in addition to the existing ones [2]. Cancer is a disease that is characterized by proliferation of the body cells, due to failures in cellular modulation and obstruction of cell cycle progression, and thereby eliciting malignant tumor cells formation with the possibility of becoming metastatic [3].
Plant extracts are widely used in Nigeria as important sources of chemotherapeutic agents in spite of the use of synthetic drug by vast majority of the populace. Medicinal plants have been in continuous use over the years for the management of cancer [4], particularly, in most developing countries of the world including Nigeria. The use of synthetic drugs for the treatment of cancer is often accompanied by toxic side effects. Thus, the alternative use of readily available and inexpensive medicinal plants is the panacea to the toxic side effects associated with synthetic drugs [5]. These medicinal plants are made up of bioactive compounds that are responsible for their pharmacological actions in the human body.
Notwithstanding the fact that many anticancer agents have been derived from medicinal plants, many plants with anticancer potentials are yet to be discovered. There are over 114,000 plant extracts that are being analyzed for their anticancer activity in various cancer institutes. Accordingly, there is a pressing need to carry out conclusive investigations to establish whether these extracts exhibit anticancer activity and applied as chemotherapeutic agents [12,13].
One of the major approaches towards new drug discovery is applying the knowledge of ethnobotanical properties of medicinal plants; the so-called ethnobotanical bioprospecting [14][15][16][17][18]. This common approach, which is based on specific traditional uses of herbs in Nigeria, depends majorly on the extent at which the herb was able to cure a particular disease among the populace. Ethnomedicinal practices are usually transferred from one generation to another, and thus, serve as an effective and reliable guide towards the identification of plants that exhibit anticancer activity.
The present review summarized the anticancer activity of Nigerian medicinal plants that have been empirically investigated. The review also highlighted the plant parts and bioactive compounds responsible for the anticancer activity as well as their possible pharmacological actions.

Main text
Information and data acquisition The information and data used in this review were sourced from scientific databases such as Google Scholar, PubMed, SpringerLink, Medline, ScienceDirect, and Mendeley. Publications from 1972 to 2020 were retrieved from these scientific search engines giving rise to 254 references that were cited in this report.

The Nigerian medicinal plants with promising anticancer activity
This review highlighted 51 anticancer medicinal plants that are widespread in all regions of Nigeria. Furthermore, the proposed anticancer pharmacological actions as well as the anticancer bioactive compounds, the type of cancer cell inhibited, the plant parts responsible for the anticancer activity, and the nature of the extracts used for the studies were reported and are summarized in Table 1.

Acronychia baueri (Rutaceae)
The aqueous bark extract of A. baueri has been reported to exhibit remarkable antitumor activity. The antitumor activity of the bark of A. baueri was due to the presence of alkaloids (normelicopidine, melicopine, acronycine) and triterpene lupeol, whereby acronycine exhibited the highest antitumor activity [19].

Ageratum conyzoides (Compositae)
The cytotoxicity of ethylacetate extract of A. conyzoides on A549 (lung carcinoma) and P388 (leukemia) cell lines in humans and mouse, respectively, has been reported [20]. The leaf extract of A. conyzoides also inhibited the proliferation of SF-767, LNCaP, PC-3, and SF-763 cancer cell lines [21]. The anticancer effect of the leaf extract of A. conyzoides was reported to be as a result of the presence of the anticancer compounds: kaempferol, oxygenated terpenes, sesquiterpene hydrocarbons, and monoterpene hydrocarbons [20,21].

Alchornea cordifolia (Euphorbiaceae)
The methanolic leaf extract of A. cordifolia initiated cell death through the activation of caspases, damage of the mitochondrial membrane, and stimulation of reactive oxygen species (ROS) generation in adriamycin-sensitive leukemia (CCRF-CEM cells). The methanolic bark extract of A. cordifolia was also reported to have deleterious effects on CCRF-CEM cells [22]. The bioactive compounds isolated from A. cordifolia with possible anticancer potentials include the flavonoids, saponins, cardiac glycosides, steroids, anthraquinone, terpenes, xanthones, alkaloids, and tannins [23].

Allium sativum (Amaryllidaceae)
A. sativum L., also known as garlic, is a rich source of Sallylcysteine and S-allylmercapto-L-cysteine. These bioactive compounds are known to exhibit high radical scavenging activity, which is essential in the inhibition of cancer development. S-allylcysteine also retarded tumor growth [24]. Additionally, A. sativum repressed the proliferations of skin, colon, lung, prostate, leukemia, and breast cancer cells in vitro [25,26].

Aloe barbadensis (Asphodelaceae)
Ethanol extract of A. barbadensis (Aloe vera) exhibited antitumor activities through the modulation of lipid peroxidation and stimulation of the antioxidant defense system in mice [27,28]. The anticancer activity of A. barbadensis was attributed to aloe-emodin, which was identified in leaf extract of the plant. This bioactive compound exhibited cytotoxicity in hepatoma cell and neuroectodermal tumors, as well as lung squamous cell carcinoma [27]. The cytotoxicity of A. barbadensis against HepG2 and HCC cancer cell lines has also been reported [28].
Alstiboonine is another bioactive compound from stembark of A. boonei that has been noted to exhibit deleterious effects on cancer cells [29].

Anacardium occidentale (Anacardiaceae)
Hydroethanolic leaf extract of A. occidentale has shown cytotoxicity against leukemia cells. The leaf of this medicinal plant inhibited the proliferation of leukemic cancer cells and was slightly cytotoxic to the cell lines: Hep-2 (laryngeal cancer), HL-60 (leukemia), and Raji (Burkitt lymphoma). These anticancer activities were attributed to the presence of agathisflavone in the hydroethanolic leaf extract of A. occidentale [34]. According to Taiwo et al. [35], methyl gallate, anacardicin, zoapatanolide A, and agathisflavone exhibited cytotoxicity against HeLa (cervical cancer) cells. Furthermore, Obembe and Ige [36] noted that the stem-bark and leaves of A. occidentale are rich sources of the anticancer compounds such as tannins, alkaloids, saponins and polyphenols.

Anogeissus leiocarpus (Combretaceae)
The inhibition of cancer cell proliferation by leaf and root extracts of A. leiocarpus have been reported by Olugbami et al. [37] and Salau et al. [38], respectively. The ethanolic leaf extract of A. leiocarpus hindered the proliferation of liver carcinoma HepG2 cell lines [37], whereas the root extract hindered Ehrlich ascites carcinoma cell lines [38]. Ellagic acid, castalagin, and flavogallonic acid are bioactive compounds known for their cancer cell proliferation inhibitory activity and have been isolated from A. leiocarpus [39][40][41].

Astragalus membranaceus (Fabaceae)
Root extract of A. membranaceus exhibited antitumor activity in vitro and in vivo through its cytostatic activity in myeloid and macrophage-like tumors. This plant also repressed syngeneic tumor development. The potency of root extracts of A. membranaceus to restore the functionality of T cells in cancer patients has been ascertained and reported [42]. A. membranaceus inhibited the proliferation and induced the apoptosis of breast cancer cell lines (MDA-MB-231, MCF-7, and SK-BR-3). The bioactive compounds, namely, isoflavones, calycosin, ononin, formononetin, and campanulin, have been isolated from A. membranaceus and established to be potent anticancer agents [43].

Atractylis lancea (Compositae)
The ethanol extract of A. lancea inhibited the proliferation of Hep-G2 liver cancer cell lines in vitro and induced apoptosis through the restriction of G1-phase cell cycle, disruption of mRNA, and protein synthesis, and thereby retarded telomerase action [44]. The petroleum ether root extract of A. lancea was reported to inhibit the growth of gastric cancer cell lines (SGC-7901 and BGC-823) through the blockage of the cell cycle and apoptosis. Polyacetylenes, sesquiterpenes, and sesquiterpene lactones are the major bioactive compounds from petroleum ether root extract of A. lancea with potential anticancer activity [45].

Azadirachta indica (Meliaceae)
Leaf and seed extracts of A. indica inhibited the proliferation of cancer cells as well as induced the death of cancer cells by autophagy and apoptosis. The inhibition of cancer cell proliferation was achieved and sustained by A. indica through obstruction of cell cycle progression [28,46,47]. The leaf and seed extracts of A. indica stimulated the apoptosis of leukemia, colon, breast, cervical, hepatocarcinoma, choriocarcinoma, stomach, and prostate cancer cells [48,49,100,[187][188][189]. The seed oil of A. indica inhibited the proliferation of HeLa cervical and prostate cancer cells [50,51]. The major classes of bioactive compounds responsible for the anticancer activity of A. indica include the flavonoids, phenolics, limonoids, and triterpenoids. The ethanolic leaf extract of A. indica repressed the development of PC-3M-luc2 and C4-2B prostate cancer cells in vitro [52]. Generally, A. indica has been effective in the repression of skin, prostate, breast, cervical, leukemia, liver, colon, lung and stomach cancers [53,54].

Boerhaavia diffusa (Nyctaginaceae)
The ethanolic extract of B. diffusa has been reported to block the cell cycle at the S-phase as well as destroy HeLa cell lines. B. diffusa also hindered the proliferation of cancer cells in mice through free radical scavenging activity [55]. The cytotoxic activity of the methanolic leaf extract of B. diffusa against breast cancer (MCF-7) cell lines was established by Muthulingam and Chaithanya [56]. Alkaloids, flavonoids, tannins, saponins, terpenes, anthraquinones, and steroids have been identified to be present in B. diffusa extract and are considered to be responsible for the anticancer activity of the plant [57].
Other bioactive compounds from C. cajan with promising anticancer activity include the stilbenoids and flavonoids [62,63].

Cassia occidentalis (Fabaceae)
The study done by Bhagat and Saxena [69] elucidated the anticancer activity of aqueous extract of C. occidentalis. According to the study by Bhagat and Saxena [69], aqueous extract of C. occidentalis inhibited the proliferation of SW-620 (colon cancer), HCT-15 (colon cancer), OVCAR-5 (ovarian cancer), SiHa (cervical cancer), MCF-7 (breast cancer), and PC-3 (prostate cancer) cell lines. However, Bhagat and Saxena [69] did not isolate and identify the specific bioactive compounds responsible for the anticancer efficacy of aqueous extract of C. occidentalis. Nevertheless, in general terms, the anticancer activity of C. occidentalis have been linked to the presence of the following classes of bioactive compounds isolated from C. occidentalis: the flavonoids, tannins, alkaloids, anthraquinones, and saponins [70].
Citrus aurantifolia (Rutaceae) C. aurantifolia has been reported to activate the release of caspase-3 for proapotosis and inhibit the progression of tumor cell cycle at the S-phase [78]. Additionally, C. aurantifolia increased the concentration of tumor infiltrating CD8+ T lymphocytes, and thereby strengthened immunity against cancer cells. C. aurantifolia also hindered the release of BclxL and Mcl-1 (proteins that inhibit apoptosis) [78]. Polymethoxyflavones, which is present in aqueous extract of C. aurantifolia, mitigated cancer cell metastasis through the inhibition of cell adhesion and invasion [79]. These bioactive compounds also initiated the release of NK cells leading to the lysis of cancer cells. C. aurantifolia suppressed the action of cyclin-dependent kinases (Cdk) and thereby limited the progression of tumor cell cycle at the G1-phase [79,80]. C. aurantifolia extract repressed colon SW-480, pancreatic Panc-28, and breast MDA-MB-453 cancer cells growth [81,82].

Cryptolepis sanguinolenta (Asclepiadaceae)
The aqueous root extract of C. sanguinolenta has shown potency to suppress V79 cell lines (lung fibroblast cells). This effect has been attributed to cryptolepine (an alkaloid), which vastly occurs in C. sanguinolenta. Cryptolepine acts by inhibiting the proliferation and viability of cancer cell lines including V79 [84]. Other alkaloids with anticancer activity from C. sanguinolenta include ascryptolepinoic acid, quindoline, and methyl cryptolepinoate [85].

Curcuma longa (Zingiberacea)
The rhizome of C. longa (turmeric) inhibited the growth of cancer cells and also caused the extermination of lymphoma cells and lymphocytes. The anticancer activity of C. longa was attributed to curcumin present in the rhizome [86]. According to Huang et al. [87], C. longa repressed the proliferation of cancer cells and prevented forestomach cancerous growth in animals. The antioxidant and anti-inflammatory activity of C. longa makes it a suppressor of breast, colon, lung and liver cancer cells. Curcumin has also shown obstructive activity against cancer cell signaling phases [88]. Generally, curcumin stimulated the apoptotic pathway, initiated cell cycle arrest, and hindered the protein tyrosine kinase activity and the manifestation of c-myc mRNA and bcl-2 mRNA [89]. Ahmad et al. [90] reported the anticancer activity of the ethanolic rhizome extract of C. longa against MDA-MB-231 human breast cancer cell line.

Derris scandens (Fabaceae)
Ethanolic extract of D. scandens was reported to repress human colon cancer HT29 cells in concert with radiosensitization. Furthermore, D. scandens provoked HT29 cells death through apoptosis and mitotic inhibition when augmented with γ-irradiation. D. scandens also acts by suppression of Erk1/2 activation [91]. Certain isoflavones isolated from D. scandens with anticancer potentials include glyurallin, derriscandenon B and C, isochandaisone, and derrubone [92].

Enantia chlorantha (Annonaceae)
The methanolic stem-bark extract of E. chlorantha suppressed the proliferation of human colorectal adenocarcinoma (DLD-1 cell line) and human mesothelioma (SPC212 cell line) as well as HepG2 liver cell line [93]. According to Musuyu et al. [94], the stem-bark extract of E. chlorantha had deleterious effects on human lung fibroblast cell line. Columbamine, saponins, pseudocolumbamine, and palmatine have been isolated from E. chlorantha and were considered to be the anticancer agents in E. chlorantha [95].

Fagara zanthoxyloides (Rutaceae)
Root extract of F. zanthoxyloides is a rich source of fagaronine. This bioactive compound is cytotoxic to human leukemia [96]. The aqueous root extract of F. zanthoxyloides reduced the viability and hindered the proliferation of the following prostate cancer cell lines: PC-3, CWR-22, LNCaP, and DU-145 [97].

Glochidion zeylanicum (Euphorbiaceae)
The triterpinoids and megastigmane glycosides from stem-bark and leaf extracts of G. zeylanicum, respectively, inhibited tumor development, whereas the methanolic root extract was cytotoxic against human cancer cell lines including PC-3. The aqueous root extract of G. zeylanicum also suppressed human prostate cancer PC-3 cell line, human colon cancer HT29 cell line, and human liver cancer HepG2 cell line [8,98,99].

Glycyrrhiza glabra (Fabaceae)
Licochalcone vastly occurs in G. glabra. This bioactive compound exerted apoptotic activity against prostate cancer cells and caused obstruction of the cell cycle through the repression of G2/M cells, cdc2, and cyclin B1. G. glabra reduced the levels of cyclin D1 and the transcription factor E2F, raised cyclin E levels and inhibited CDK 4/6 [101]. Another bioactive compound, isoliquiritigenin, isolated from G. glabra, suppressed prostate cancer proliferation. Isoliquiritigenin initiated the arrest of S-and G2/M-phases and also induced GADD153 mRNA and protein functions that are involved in cell cycle arrest [100]. The aqueous extract of G. glabra exerted anticancer activity against breast cancer (MCF-7) and colon cancer (HT-29) cell lines [102].

Goniothalamus macrophyllus (Annonaceae)
The bioactive compound, goniothalamin, from G. macrophyllus exhibited cytotoxic activity against cervical cancer cells (HeLa), through the initiation of DNA fragmentation and damage as well as the activation of caspase-9, leading to apoptosis [103]. The methanolic root and stem extracts of G. macrophyllus were highly cytotoxic against breast MCF-7 and colon LS-174T cancer cell lines [103,104]. These anticancer activities of G. macrophyllus were attributed to goniothalamin [104].

Harungana madagascariensis (Guttiferae)
Stem extracts of H. madagascariensis induced the release of nitric oxide, which plays major role in cancer chemotherapy [105]. The methanol as well as the dichloromethane stem-bark extract of H. madagascariensis suppressed the growth of CCRF-CEM cancer cell lines [106]. The following bioactive compounds with anticancer potentials have been identified in H. madagascariensis: coumarins, anthraquinones, bioflavonoids, anthrone derivatives, and xanthones [107].

Lophira alata (Ochnaceae)
The methanol stem-bark extract of L. alata was reported to repress the activity of Epstein-Barr virus (EBV) as well its early antigen, and thereby preventing the development of tumors [113]. The anticancer activity of L. alata was attributed to bioactive compounds such as azobechalcone A, flavonoids, isolophirachalcone, and lophirone F, which have been isolated from stem-bark of the plant as described by Murakami et al. [114]. The bioactive compound, lophirone A, which is present in L. alata retarded tumor growth [113]. Triterpenes, sterols, and polyphenols isolated from the stem-bark of L. alata were also reported to be cytotoxic against HepG2, A549, SPC212, CRL2120, MCF-7, and DLD-1 cell lines [93]. Lophirones C and Lophirones B that occurs in stembark of L. alata inhibited the proliferation of Ehrlich ascites carcinoma cells [115].

Panax ginseng (Araliaceae)
Ginsenoside Rp1 from P. ginseng inhibited the insulinlike growth factor 1 receptor and thereby prevented human breast cancer cells from multiplying as well as disrupted the anchorage of cells colony. This bioactive compound also induced cell cycle arrest and repressed the growth of cells through apoptosis [141]. The roots and rhizomes of P. ginseng have also been reported by Kim et al. [142] to inhibit the proliferation of MCF-7 breast cancer cell lines.

Phyllanthus amarus (Euphorbiaceae)
P. amarus extracts have been reported to initiate apoptosis of cancer cells. P. amarus caused obstruction of the G0/G1-phase and S-phase in PC-3 and MeWo cell lines, respectively, and hindered the invasion, migration, and adhesion of these cell lines [143,144]. Generally, the methanolic extract of P. amarus was cytotoxic to lung, breast, pancreas, neuroblastoma, skin, ovarian, glioblastoma, and prostate cancer cell lines. Flavonoids, ellagitannins, polyphenols, triterpenes, sterols, phyllanthin, saponins, and alkaloids have been isolated from P. amarus and have been reported to promote anticancer activity [145].

Phyllanthus emblica (Phyllanthacae)
The aqueous extract of P. emblica was cytotoxic against human fibrosarcoma cells (HT1080) by interrupting the invasion, movement, adhesion, and growth of the cells at low level of IC50 [146]. Ellagic acid, chebulagic acid, and gallic acid were among the most studied anticancer bioactive compounds from P. emblica and are known to exhibit antioxidant properties [147][148][149]. The ethanolic fruit and leaf extracts of P. emblica inhibited cancer cell proliferation as well as reduced the viability of HT-29 colon cancer cell line [150]. Mahata et al. [151] reported the efficacy of the fruit extract of P. emblica against cervical cancer cells in vitro.

Picrorhiza kurroa (Plantaginaceae)
P. kurroa root extract is known to be cytotoxic against cancer cells. The anticancer activity of P. kurroa root extract was attributed to the bioactive compounds, namely, apiocynin, cucurbitacines aglycone, and caffeic esters [152]. Picrosides isolated from P. kurroa was reported to possess anticancer activity by its anti-inflammatory and antioxidant actions [153]. The hydroalcoholic extract of P. kurroa was reported to be cytotoxic against cervical HeLa, SiHa, and breast MCF-7, MDA-MB 231 cancer cell lines [154].

Psidium guajava (Myrtaceae)
The study carried out by Ryu et al. [155] revealed the anticancer potency of n-hexane leaf extract of P. guajava. The extract induced cell death in prostate PC-3 cancer cell lines through the interruption of the signaling activity associated with tumor formation. The inhibition of the proliferation of breast MCF-7, leukemia P388, prostate DU-145, cervical KB, and HeLa cell lines by the leaf extract of P. guajava has also been reported [156]. The anticancer potency of P. guajava has been linked to the bioactive compounds, namely, cryptonine, tannins, apigenin, dihydrobenzophenanthridine, lycopene, and saponins present in the plant [156].

Punica granatum (Lythraceae)
P. granatum is rich in ellagic acid and ellagitannins. These bioactive compounds are metabolically transformed to urolithins in the gut microbiota. Urolithins disrupted the cell cycle, prevented cancer cell proliferation, and stimulated apoptosis [80]. The ellagitannin in P. granatum extract repressed colorectal cancer in patients [157]. The aqueous fruit extract of P. granatum inhibited the proliferation of colon cancer cell lines including HT29, SW620, SW480, and HCT116 [39]. The anticancer activity was attributed to the presence of ellagic acid and punicalagin as well as tannins in P. granatum [39].

Rauvolfia vomitoria (Apocynaceae)
Ethanolic root extract of R. vomitoria has been reported to be cytotoxic to pancreatic, prostate, and ovarian cancer cells [158][159][160]. The ethanolic root extract of R. vomitoria initiated apoptosis and hindered the expansion of tumors in pancreatic cells according to the study done by Yu and Chen [160]. This anticancer activity was attributed to the presence of β-carboline in R. vomitoria. Furthermore, R. vomitoria extract repressed the proliferation as well as induced cell cycle arrest in prostate cancer cells [158]. Additionally, ethanolic root extract of R. vomitoria inhibited the development of ovarian cancer cell lines (OVCAR-8, OVCAR-5, SHIN-3) and also initiated apoptosis of cancer cells [159]. Other anticancer bioactive compounds identified in R. vomitoria include terpenes, tannins, alkaloids, steroids, saponins, and flavonoids [161].

Tabebuia avellanedae (Bignoniaceae)
β-Lapachone is a bioactive compound present in the stem-bark of T. avellanedae and has shown high efficacy to ameliorate cancer. Specifically, β-lapachone hindered the development of HepG2 hepatoma cell line in vivo through DNA fragmentation and the synthesis of apoptotic bodies. This bioactive compound repressed the proteins Bcl-2 and Bcl-XL and also stimulated the action of Bax, thus supporting apoptosis. β-Lapachone from T. avellanedae also caused the activation of poly (ADP-ribose) polymerase protein and caspase-3 and caspase-9 [165].

Thymus vulgaris (Lamiaceae)
El-khamissi et al. [166] reported the cytotoxic activity of ethanol peel extract of T. vulgaris bulb in human breast cancer MCF-7 cell lines. Other bioactive compounds such as diallyl disulfide, diallyl trisulfide, and allicin isolated from T. vulgaris have also shown high potency in the suppression of cancer cells [26].
T. vulgaris oils stimulated the extermination of cancer cells by controlling interferon signaling and the biosynthesis of N-glycan as well as the extracellular signalregulated kinase 5 signaling [167]. According to the study by Soomro et al. [190], the butanol leaf extract of T. vulgaris exhibited slight anticancer activity against HeLa cervical cancer cell lines. This anticancer activity of T. vulgaris was attributed to the bioactive compounds such as tannins, triterpenes, sterols, flavonoids, and glycosides isolated from this plant.

Tinospora cordifolia (Menispermaceae)
T. cordifolia has been used in vitro to exterminate HeLa cancer cells, which confirms the anticancer activity of T. cordifolia [168]. The dichloromethane extract of T. cordifolia exhibited high efficacy against cancer cells in mice [168]. The methanolic stem extract of T. cordifolia elicited cytotoxicity and inhibited the proliferation of human breast cancer cell line (MDA-MB-231) in the study carried out by Ahmad et al. [169]. The anticancer bioactive compounds identified in T. cordifolia include epoxycleodanediterpene, arabinogalactan, berberine, and phenolics [170].

Tithonia diversifolia (Compositae)
The ethanolic and methanolic leaf extracts of T. diversifolia inhibited the proliferation of HL-60 and U373 cancer cell lines, respectively [171,172]. Bioactive compounds such as tagitinin C, 1β-methoxydiversifolin 3-O-methyl ether, 1β and 2α-epoxytagitinin C are the major anticancer agents present in T. diversifolia and were involved in the inhibition of human Col2 colon cancer cells proliferation and cell death [173]. The methanolic leaf extract of T. diversifolia contains tagitinin C, which suppressed G2/M, reduced cancer cell viability, and stimulated cancer cell autophagy. Tagitinin C was also reported to be responsible for the anticancer activity of methanolic leaf extract of T. diversifolia [174].

Vernonia amygdalina (Compositae)
Studies showed that V. amygdalina extracts inhibited the proliferation of BT-549 and MCF-7 breast cancer cell lines [176]. Steroid glycosides have been linked to the anticancer agent of V. amygdalina [176]. The chloroform extract of V. amygdalina suppressed KB cell lines. The peptide known as edotide in the leaves of V. amygdalina inhibited breast cancer [176][177][178].

Zanthoxylum nitidum (Rutaceae)
The root of Z. nitidum is a rich source of nitidine. Nitidine is an anticancer agent that acts as an inhibitor of topoisomerases I and II activities [179,180]. Benzophenanthridine isolated from Z. nitidum roots was reported to exert cytotoxic and antiproliferative activities against lung (A549), cervical (HeLa), and liver (SMMC-7721) cancer cell lines [181].

Classifications of bioactive compounds with anticancer activity
The major classes of bioactive compounds from medicinal plants with anticancer activity include the polyphenols, flavonoids, alkaloids, saponins, triterpenes, tannins, and quinones. These bioactive compounds exerted antiproliferative, cytotoxic, cytostatic, antimetastatic, apoptotic, and antioxidative actions as well as provoked cell cycle arrest, inhibited angiogenesis and reduced cancer cell viability.

Polyphenols
Polyphenols have been reported to possess antioxidant and cytotoxic activities against cancer cells [191][192][193]. The anti-carcinogenicity of the polyphenols is hinged on their capabilities to initiate apoptosis. Polyphenols regulate the assemblage of copper ions on chromatin. The copper ions assemblies on chromatin, engendered by the polyphenols such as resveratrol, elicit DNA disintegration [191].
Plant polyphenols also interacted and interfered with cancer cells proteins and thereby inhibited the growth of these cells. Polyphenols bonded directly with cancenogens disrupted their cancer promoting activities through acetylation, phosphorylation, and methylation mechanisms. For instance, a polyphenol-curcumin was reported to suppress the actions of tumor necrosis factor (TNF) in cell lines [194]. Curcumin also stimulated the apoptotic pathway, initiated cell cycle arrest and hindered the protein tyrosine kinase activity as well as the manifestation of c-myc mRNA and bcl-2 mRNA [89].

Flavonoids
The flavonoids were reported to be toxic to cancer cells and exhibited high free radical scavenging activity [195]. The following flovonoids, alpinumisoflavone and 4'methoxy licoflavanone, initiated the apoptosis of human leukemia via extrinsic and intrinsic signaling pathways; the mitochondria of the cell were destroyed in the process, and thereby lead to cell death [196]. Xia et al. [197] reported the high anticancer efficacy at low concentrations of the flavonoids.
The flavonoids hindered NF-ĸB expression. NF-ĸB is a protein complex that is required for the angiogenesis, proliferation and survival of cancer cells [198]. The flavonoid, isoliquiritigenin, induced the obstruction of S-phase and G2/M-phase as well as activated GADD153 mRNA and protein functions involved in cell cycle arrest [100].

Alkaloids
These bioactive compounds disrupted tumorigenesis as well as the progression of tumor cell growth [199][200][201]. The alkaloids inhibited cancer cells proliferation through the initiation of cell apoptosis and by stimulating the termination of cancer cell cycle at G1-phase or G2/Mphase [199,202,203]. The alkaloids induced cancer cell autophagy and endoplasmic reticulum damage [202,204]. The alkaloids elicited their anticancer efficacy majorly by acting as inhibitor of tumor invasion and metastasis [205,206]. Jie et al. [207] and Hamsa and Kuttan [208] reported the ability of alkaloids to inhibit tumor angiogenesis. These bioactive compounds reduced cellular glutathione (GSH) levels by interacting directly with GSH and thus stimulated the generation of ROS [209][210][211][212]. The alkaloids are also involved in the inhibition of NF-κB activation [199,202].

Saponins
Saponins exhibited immunomodulatory activities through cytokine interplay [199]. Cytotoxic and cytostatic actions were among the major anticancer mechanisms of saponins [213,214].
The triterpene saponins repressed the growth of cancer cells and activated apoptosis [215]. Saponins exerted antiproliferative activity by clustering in the S-phase and causing G2/M-phase obstruction, as well as the inhibition of the expression of p21 and the cyclin-dependent kinase activity. Saponins activate cancer cell apoptosis through the stimulation of caspase-3 and caspase-9, and the disintegration of poly (ADP-ribose) polymerase accompanied by DNA fragmentation and condensation of nuclear chromatin [216,217]. The steroidal saponins promoted cancer cell cycle arrest and induced apoptosis, as well as acted as antitumor agents [218]. The saponins, ginsenoside Rp1, induced cancer cell cycle arrest through the repression of G2/M cells, cdc2, and cyclin B1 [102].
Triterpenes induced cell cycle arrest at the G2/M-, G1-, and S-phases by mitigating cyclin Bi/cdc2 action, upregulation of P21 effect and the repression of cyclin A expression, respectively [221,224,227]. Triterpenes hindered the proliferation of tumor cells through the obstruction of the Akt/mTOR signaling pathway [228,229]. Triterpenoids hindered the invasion and migration of cancer cells by mitigating the expression of the proteins MMP-2 and MMP-9 as well as gelatinase activity [230]. This class of bioactive compounds suppressed tumor angiogenesis by inhibiting the secretion of the angiogenic factors: bFGF and VEGF-A and the vascular endothelial growth factor [231,232].

Tannins
The anticancer pharmacological actions of the tannins, such as ellagiatannin, have been reported to be involved in cyclin E upregulation and cyclins A and B1 downregulation, cell cycle obstruction at the S-phase, and apoptosis activation through the intrinsic pathway by downregulating bcl-XL accompanied by the cytosolic mitochondrial secretion of cytochrome C, as well as induction of caspase-3 and caspase-9 [233].
According to Jia et al. [234], tannins such as corilagin exhibited anti-inflammatory action, inhibited the growth of cancer cells by obstructing the TGF-β/AKT/ERK/Smad signaling pathways, as well as induced cell cycle arrest at the G2/M-phase. Tannins also elicited apoptosis of cancer cells through the stimulation of sub-G1 fraction and condensation of chromosome as well as DNA disintegration [235].

Quinones
Quinones such as aloe-emodin inhibited the proliferation of cancer cells through the obstruction of the following cell cycles: G1-, G2/M-or S-phases [236][237][238][239][240]. Quinones stimulated DNA damage by inducing ROS [241]. Quinones activated cancer cell apoptosis by stimulating c-Jun N-terminal kinase, caspases, the Fas pathway and p53 pathway [236,240,242,243]. The anticancer activity of the quinones has also been attributed to the ability of these bioactive compounds to mitigate the expression of urokinase, MMP-2 and MMP-9 proteins as well as nuclear translocation inhibition [139,244,245]. The quinone, β-lapachone, was reported to induce DNA fragmentation and the synthesis of apoptotic bodies, repressed the proteins Bcl-2 and Bcl-XL and stimulated the action of Bax, and thereby promoted cancer cell apoptosis, activated poly (ADP-ribose) polymerase protein and caspase-3 and caspase-9 [165].

Anticancer drugs derived from Nigerian medicinal plants after undergoing research and clinical trials
Drugs derived from medicinal plant in the form of herbal remedies are preferred to synthetic drugs for the treatment of cancer because; for the most part, they are associated with fewer side effects, inexpensive, and readily available. These herbal remedies can be easily consumed as components of the patient's dietary intake [246,247]. The anticancer activity of medicinal plants are dependent on their bioactive compounds, although some of these bioactive compounds such as lectins, some taxanes, cyanogenic glycosides, and lignans are less tolerated and toxic to humans [248,249]. Nevertheless, research has also shown that plants derived drugs exhibited anticancer activity with little or no toxic effects on normal cells and have been subjected to clinical trials for the development of therapeutics [247].
The anticancer drugs derived from Nigerian medicinal plants that have undergone various stages of research and clinical trials include paclitaxel (Taxol), vinblastine, vinflunine, vinorelbine, vindesine, vincristine, pomiferin, epigallacotechin-3-gallate, sulphoraphane, flavopiridol, epipodophyllotoxin, combretastatin A-4 phosphate, noscapine, and roscovitine. The Nigerian plants from which anticancer drugs are derived, the bioactive compounds that exert the anticancer activity as well as the associated pharmacological actions are presented in Table 2.

Conclusion
In this review, the 51 Nigerian medicinal plants were reported to exhibit anticancer activity of the prostate, cervices, lung, skin, colon, esophagus, blood, ovary, central nervous system/brain, breast, stomach, pancreas, larynx, and kidney, indicating the possible use of these medicinal plants as anticancer drug agents. The major classes of bioactive compounds indicated to be responsible for the anticancer activity include the polyphenols, flavonoids, alkaloids, saponins, triterpenes, tannins, and quinones. The major anticancer pharmacological actions of these bioactive compounds were antiproliferative, cytotoxic, cytostatic, antimetastatic, apoptotic, and antioxidative as well as provoked cell cycle arrest, inhibition of angiogenesis and reduction of cancer cell viability. This review also reported 14 anticancer drugs derived from Nigerian medicinal plants that have undergone various stages of research and clinical trials. These anticancer drugs include paclitaxel (Taxol), vinblastine, vinflunine, vinorelbine, vindesine, vincristine, pomiferin, epigallacotechin-3-gallate, sulphoraphane, flavopiridol, epipodophyllotoxin, combretastatin A-4 phosphate, noscapine, and roscovitine. The present review showed that leaf, root, and stembark extracts of the Nigerian medicinal plants were principal sources of vast majority of bioactive compounds that exhibited anticancer activity. Therefore, further emphases on the investigations of anticancer activity of these Nigerian medicinal plants parts, namely, the leaf, root, and stem-bark extracts is recommended. Nigerian medicinal plants can be harnessed to provide for readily available and inexpensive anticancer drugs in the future because the plants reported in this review showed promising anticancer activity.