TRADITIONAL KNOWLEDGE OF CANCER TREATMENT IN SOUTHWESTERN NIGERIA: AN ETHNOPHARMACOLOGICAL REVIEW

Cancer is one of the main causes of death globally and a serious public health problem. One in every six mortalities worldwide is caused by cancer. Several chemotherapeutic medications are used to treat cancer without any selectivity, which has long-lasting negative consequences. Nigerian Medicinal Plants (NMPs) have been used in traditional and folk medicine to manage and treat cancer. The present review aims to provide a summary of the traditional knowledge of cancer treatment in Southwestern Nigeria detailing the plants, phytochemistry, the synergistic effects of synthetic and natural product drugs, the perspective of the indigenous people in the treatment of cancer, and the anticancer activity of Nigerian medicinal plants that have undergone empirical investigation. Some of these plants have been reported to exhibit anticancer activity in the breast, lung, pancreatic, stomach, colon, prostate, leukemia, ovarian, and cervical indicating the possible use of these medicinal plants as anticancer drug agents.


INTRODUCTION
Cancer is a group of several diseases that can be caused by genetic or epigenetic changes in somatic cells, resulting in abnormal cell proliferation thereby leading to damage of organs in the body.The rate of projection of cancer is about 18.1 million individuals, with one out of five men and six women being prone to develop cancer in their lifetime [1].Cancer has been known to result in death when not properly managed.Cancer death occurs mainly in developing countries, and this accounts for about 70% of cancer incidence in developed countries [2].
Even though the great majority of the population uses synthetic medications, plant extracts are still frequently employed in Nigeria as essential sources of chemotherapeutic agents.Over the years, medicinal plants have been used continuously to treat cancer [3].
Applying the understanding of the ethnobotanical qualities of medicinal plants is one of the main methods for finding novel drugs; this process is known as ethnobotanical bioprospecting [4,5].This typical approach, which is based on distinct traditional applications of herbs in Nigeria, is heavily reliant on how well the herb was able to treat a certain condition among the people.The discovery of plants that have anticancer potential can be aided by using ethnomedical traditions, which are often passed down from generation to generation.
Due to the enormous chemical complexity seen in thousands of plant species, nature is a major source and still an attractive source of possible medicinal candidate molecules.Currently, several compounds originating from plants are used very successfully in the treatment of cancer [6].
Chemotherapy poses serious risks to healthy tissues.Podophyllotoxin's discovery in the late 1960s prompted the search for natural cancer treatments and resulted in the development of anticancer drugs including vincristine, vinblastine, camptothecin, and taxol [7].
Nigerian Medicinal Plants (NMPs) have been used in traditional and folk medicine to manage and treat cancer [8]; although there hasn't been much research to support their cytotoxicity, they may be more advantageous and less expensive than traditional pharmaceuticals.
Recently, research on the production of novel and effective anticancer compounds has been centered on medicinal plants [9].
It is therefore pertinent to document the knowledge of traditional medical practitioners in the treatment of cancer.This will serve as a guide to researchers in drug discovery from natural sources.
The present review detailed the traditional knowledge of cancer treatment in Southwestern Nigeria.This review also summarizes the anticancer activity of Nigerian medicinal plants that have been empirically investigated, the plant parts, the synergistic effect of synthetic and natural product drugs, the perspective of the indigenous people in the treatment of cancer, and the isolated compounds responsible for the anticancer activity.

Types of cancer
The constant exposure to radiation could lead to the deposition of radioactive materials into the lungs, and skin, thereby causing mutation and then tissue damage.This in turn can lead to different forms of cancer [10,11].Cancer in both genders and across all age groups can affect all body sites.Globally, breast cancer seems to be the most common type of cancer with a high rate of death in low and middleincome countries [12,13].The incidence of death because of breast cancer was estimated to be the highest in Africa [14].This could be because of insufficient awareness, poor health systems, and sometimes low levels of female education [15,16].Lack of information about symptoms and possible early diagnosis has been identified as prominent factors influencing the survival rates of patients with breast cancer [17,18].
Cervical cancer has been ranked the second most commonly occurring cancer among women in Nigeria with a large percentage of cancer death occurring in developing countries [19][20][21].Infection by human papillomavirus has been established to cause cervical cancer in women.This can be prevented early if discovered and prevented by vaccination.The incidence could be because of unawareness, exposure to human papillomavirus, and sometimes the unavailability of vaccines in the country [22,23].The cultural belief of individuals has made vaccination impossible [24].It has been estimated that yearly, over 12,000 women are diagnosed with cervical cancer and about 8,000 patients will die [25].

Causes of Cancer
Several individuals have been reported to have one way or another been affected by cancer during their lifetime.This could be as a result of exposure to pollutants viz some agricultural pesticides with toxic constituents for example, chlorophenols, and phenylacetic acid which are found to have carcinogenic effects on the lungs [26,27].environmental pollutants, and infection [28].
Heredity is also a major cause of cancer.The mutation of genes such as BRCA1 and BRCA2 is estimated to account for the incidence of ovarian and breast cancers globally [29].In Nigeria, the occurrence of breast cancer is a result of the mutation of the genes [30].

Methods of Cancer Treatment
Individuals with cancer are more likely to respond to treatment of cancer if there is an early detection.Thus, there is a great chance of survival with a reduced cost of treatment if a delay in care is avoided [1].
Treatment of cancer could range from surgery, radiotherapy, chemotherapy, and immunotherapy [31,32].This is dependent on the stage in which the diagnosed.

Synergistic effect of synthetic and natural product drugs
The presence of polyphenols and flavonoids in Achillea odorata extract responsible for the antioxidant properties of the plant showed significant cytotoxicity, inhibition of cell proliferation against breast, human epiglottis, and mouse leukaemia (MCF-7, Hep 2 and WEHI) cancer cell lines.The cytotoxicity observed was with varying percentages of inhibition [46].
Cisplatin (CDDP), used for the treatment of malignancies has been of high efficacy during chemotherapeutic management of cancer but with the efficiency, several side effects which include nephrotoxicity have been reported [47,48].With this, it is necessary to consider drugs that will protect the kidney from toxicity since ultrafiltration is primarily carried out by the kidney.Recently, the antioxidant properties of Ficus carica (L.) leaf extract have been utilized for the reduction in acute kidney injury observed upon treatment with cisplatin.A significant reduction in the concentration of urea, creatinine, oxidative stress marker, and malondaldehyde for lipid peroxidation [49].Also, an increase in the white blood cell count and pro-inflammatory cytokine, TNFα were observed in the group treated with the plant as compared with CTX.This study further confirmed the immune-stimulatory and antitumor activity of C. orchioides [51,52].

The perspective of the indigenous people in the treatment of cancer
Reports from the World Health Organization

Medicinal plants
Medicinal plants remain the significant basis of traditional medicine for the populace.Around 80% of people in the world rely on traditional, predominantly herbal treatments for their primary healthcare requirements [56].

Nigerian medicinal plants with promising anticancer potential
This study discovered 72 anticancer medicinal plants that are found across Nigeria's ethnobotany. In

Pharmacology of medicinal plants used for the treatment of Cancer
The cancer inhibitory effect against MCF7 cells Thus, the extracts contain antiproliferative components [68].
Crinum jagus L. bulb extract was evaluated for its cytotoxic and anti-proliferative activity.It was observed that the extract displayed higher cytotoxicity compared to the positive control; cyclophosphamide used for cancer treatment [69].The evaluation of the cytotoxic activity of Canavalia ensiformis against colon carcinoma cells was reported [70].The selectivity indices were also estimated.On Jurkat cells, the leaf extract, chloroform, and ethyl acetate fractions all showed cytotoxicity, with IC50 values of 15.10.3 g/mL, 6.36 g/mL, and 4.60 g/mL, respectively, compared to curcumin, which had an IC50 of 0.002 g/mL.
In addition, as compared to curcumin (Selective Index = 2.3), the leaf extract, chloroform, and ethylacetate fractions were highly selective against Jurkat cells, with Selective index values Cyclophosphamide (CTX) is a broad-spectrum chemotherapeutic agent usually used in combination with others or alone.Its activity is observed in the prevention or inhibition of cell proliferation which in turn induces cell or tumor death [47].Treatment with cyclophosphamide has shown several side effects which include increased suppression of immunity, via the elimination of the helper T-cells [50].The ameliorative effect of medicinal plants in combination with CTX has shown synergy in activity.Curculigo orchioides (Gaertn) belonging to Hypoxidaceae family with several pharmacological properties was selected for study to validate its anti-tumor potentials against Dalton's Lymphoma ascites and c oxidative damage caused by treatment with CTX using the swiss-albino mice induced with tumor cells.Results showed a synergistic effect between C. orchioides and CTX in the reduction of solid tumors as compared to the group treated with standard drug, CTX, alone.
showed that at least 80% of individuals in Africa rely mainly on the use of medicinal plants for healthcare delivery[53][54][55].With the knowledge of the TMPs in medicinal plants, mode of preparation, and administration of the herbal mixture, successful treatment of some chronic ailments has been established.However, standardization remains a problem because of the lack of identification of some plant materials which can pose a threat to humans.Some indigenous people have the fear of being treated in the hospital because of the mentality of the hospital staff, they also have the belief that their cultural integrity will be at a loss, and sometimes no evidence of survival of cancer patients who had hospital treatment in their society.This poses a real problem in the local settings, therefore relying on traditional medicine.
several therapeutic flora have been documented in various communities around the world, including Africa [57].Traditional use of plants for managing numerous diseases remains an essential part of the traditions of most of the populace.Furthermore, medicinal plant affordability, availability, and accessibility are important factors that have contributed to the high demand and practice.Secondary metabolites produced by plants, such as tannins, saponins, essential oils, alkaloids, and flavonoids, provide protective mechanisms that are involved in the healing properties of a variety of medicinal floras [58].Medicinal plants have a great future because there are around half a million plants on the planet, and most of them have not yet been studied for their medicinal properties [59].Even though most Nigerians utilize synthetic drugs, plant extracts are widely used as essential sources of chemotherapeutic agents.Medicinal plants have been used for the treatment of cancer for many years, particularly in most developing countries around the world, including Nigeria.Synthetic medications are frequently associated with harmful adverse effects when used to treat cancer.As a result, using readily available and inexpensive medicinal plants as an alternative to synthetic medications is the panacea for hazardous side effects [60].The bioactive chemicals in these medicinal plants are responsible for their pharmacological activities in the human body.

(
breast cancer) of the extracts of stem bark of Detarium microcarpum was previously investigated[63].The extract gave a good antiproliferative effect with IC50 78 g/mL which confirmed the ethnobotanical survey report of the plant as having anti-cancer activity.Mukavi et al.[64] also reported the in vitro cytotoxic activity of dichloromethane and methanol extracts of Kigelia africana against human breast cancer cells.The methanol extract showed higher activity (IC50: 26.02 μg/mL) compared to that of dichloromethane: methanol (1:1) (IC50: 55.01 μg/mL).The high in vitro anti-cancer activity of methanol extract of K. africana justifies its use in traditional medicine to treat breast cancer when extracted with polar solvents such as alcohol[64].The in vitro activity of the extract and fractions of Securidaca longipedunculata was assessed on the viability of U87 malignant brain tumor cell line[65].The result showed that the extract significantly (p<0.01)inhibited proliferation of U87 cell line with CC50 of 20.535 g/mL.Apoptosis was induced by the extract (41.53 ± 10.33%) and the most polar fraction (47.30 ± 2.70%) via cleavage of Poly-ADP-Ribose-Polymerase (PARP).It was concluded that S. longipedunculata root bark ethanol extracts inhibited proliferation of U87 cell line and induced apoptosis by cleavage of PARP, therefore supporting traditional use of the plant in cancer management.Dinku et al. [66] evaluated the anti-proliferative activity of crude methanol extract, n-hexane fraction, and isolated compounds commafric A and α-amyrin from Commiphora africana resin against four human cancer cell lines; the human non-small cell lung (A549), ovarian (A2780), pancreatic (MIA-Paca-2), and stomach (SNU-638).The crude extract showed a strong effect on A549 cell lines (3.55 μg/mL) among the cell lines tested.The n-hexane fraction displayed significant dose-dependent inhibition of cell proliferation on all four cell lines.Though, it showed an insignificant and a less net growth effect on A549 cell lines compared with the crude methanol extract [66].The in vitro anticancer activity of Annona senegalensis was evaluated against breast carcinoma.The crude extract of A. senegalensis was shown to exhibit a dose-dependent cytotoxic effect on breast cancer MDA-MB-231 cells.The result suggests that this plant possesses a potent anticancer effect on breast cancer cells in vitro [67].The anti-proliferative effects of aqueous extracts of Morinda lucida leaves and stems were studied in human promyelocytic leukemia (HL-60) cells.The results exhibited concentration-dependent inhibition, with CC50 values of 0.4 mg/mL and 0.171 mg/mL for Morinda lucida leaves and stems respectively.
It was discovered that both lectins inhibited the growth of HT-29 cells in a dose-dependent manner without affecting normal Human embryonic kidney 293T cells.The half-maximal inhibitory concentration value was 4.86 μg/mL.The extract from Xylopia aethiopica showed antiproliferative activity with good inhibition against a range of cancer cell lines screened.A significant percentage inhibition of 70% was observed against colon cancer cell HCT116 with an IC50 of 12 g/mL, while U937 and KG1a leukemia cells had IC50 of 7.5 g/mL and > 25 g/mL, respectively [71].Popoola et al. [72] evaluated the anti-cancer activity of Uvaria chamae using human cervical adenocarcinoma cells (HeLa), modified human breast cancer cells (AREc32, which is the MCF-7 cell line stably transfected with the antioxidant response element (ARE) reporter plasmid), human prostate cancer cells (PC3) and human lung cancer cells (A549).The extract up to 100 μg/mL was non-toxic or mildly toxic to HeLa, AREc32, PC3 and A549 cells (IC50 > 200 μg/mL) [72].Ambali et al. [61] evaluated the cytotoxicity activity of Aframomum melegueta and Strophanthus hispidus methanol extracts using Rhabdomyosarcoma (RD) and cervical; Hep-2C and normal (Vero) cell lines for the screening of the extracts.The two extracts were found to be active against the cancer cell lines and selective to the normal cell line used.The aerial part of Strophanthus hispidus gave IC50 of 2.94 ±0.01 μg/mL; its roots gave IC50 of 1.71 ± 0.04 μg/mL; and Aframomum melegueta gave IC50 of 5.18 ± 1.15 μg/mL, these extracts were more cytotoxic comparable to cyclophosphamide in RD cell line.Similar results were found in the Hep 2C cell line as regards the activity of the plants.The screening of plants on normal cell lines to determine selectivity was carried out using a Vero cell line obtained from the African Green monkey epithelial cell.Results obtained showed little or no toxicity with a selective index of 11.75, 16.17, and 20.92 against RD cell line and 6.25, 28.63, and 18.25 against Hep-2C cell line [61].Similarly, Acheampong et al. [73] evaluated the anticancer properties of hydroethanolic extracts and fractions of Ageratum conyzoides against four selected human cell lines: leukemic (Jurkat), prostate (LNCap), breast (MCF-7), and normal human prostate (PNT2) cell lines.

Table 1 [
addition, the anti-cancer activity of the most 61].

Table 2 :
Most Mentioned plants with Anti-cancer potentials in Nigeria