Medicinal plants used for treating cancer in Kenya: an ethnopharmacological overview

Cancer is one of the major causes of mortality worldwide. Though 30% of cancers can be treated when detected at early stages, their treatment has been compounded by resistance of tumor cells to anticancer drugs, side effects of the therapies, high treatment costs and limited access to medical services. In Africa, and particularly in the East African botanical plate, various ethnic groups cherish their traditions and embrace distinguished use of medicinal plants in the management of ailments like cancer. This study aimed at reviewing the ethnobotanical knowledge on the use of wild and cultivated plants as remedies for cancer treatment in Kenya as well as their phytochemical composition and reported anticancer activities. Through extensive electronic review in PubMed, Science Direct, Scopus, Google Scholar, Web of Science, Scientific Electronic Library Online and the Google search engine, 145 plant species from 125 genera spread across 55 families were found to have been reported for cancer treatment in Kenya. The malignancies treated using the herbal remedies include squamous cell carcinoma of the gum, prostate, blood, bone, breast, colorectal, colon, oesophageal, lung, liver, skin, stomach, throat and uterine cancers. Most of the identified species have reported anticancer activities, with Toddalia asiatica, Annona muricata, Carica papaya, Catharanthus roseus, Moringa oleifera, Ocimum gratissimum, Prunus africana and Zanthoxylum paracanthum being the most studied. Despite the widespread use of medicinal plants in the management of cancer in Kenya, the bioactivity, safety aspects, responsible anticancer molecules and clinical studies are required to elucidate the mechanism of action of the compounds and confirm the potential of the unstudied species.


Background
Cancer is listed among the leading causes of deaths globally and a great twenty-first century barrier to the increase in life expectancy (Chimezie and Ofure 2022; Dalmartello et al. 2021;Wekha et al. 2021).According to recent global statistics based on GLOBOCAN, about 19.3 million new cancer cases were reported in 2020.This led to at least 10 million cancer deaths (Sung et al. 2021).For this period, breast cancer was the most prevalent, with 2.3 million new cases (11.7%).The other malignances followed the order: stomach cancer (5.6%) < prostate cancer (7.3%) < colorectal cancer (10.0%) < lung cancer (11.4%).Nevertheless, lung cancer was the major cause of cancer-related mortalities accounting for about 18% (1.8 million) deaths.Colorectal (9.4%), liver (8.3%), stomach (7.7%) and breast (6.9%) cancers also made significant contributions to the estimated cancer mortalities (Sung et al. 2021).
Trickling down to the African continent, cancer has a skewed distribution and this is compounded by inadequate epidemiological expertise, diagnostic equipment and research resources, and the complex treatment seeking behavior of cancer patients (Hamdi et al. 2021).According to the National Cancer Institute of Kenya (NCI 2022), cancer is the leading cause of mortalities Page 2 of 33 Omara et al. Bulletin of the National Research Centre (2022) 46:148 in Kenya after infectious and cardiovascular diseases.Of these, breast cancer (with 5985 new annual cases or 12.5%) of all new cases is the leading cancer in Kenya (Macharia et al. 2019).The main drivers behind the increasing cancer cases in Kenya include consumption of mycotoxin and heavy metal-contaminated foods, genetic causes and residential combustion of unprocessed solid fuels such as dung, wood, charcoal and agricultural residues (Omara et al. 2021a).Coupled with antitumor drug resistance, inaccessibility and side effects of commercial drugs, indigenous communities utilize medicinal plants for managing ailments.
The World Health Organization reported that more than 80% of the emerging world's population subsists on traditional medicine for various ailments.Medicinal plants have remained an incredible source of promising drug entities (Omara et al. 2021b).Over the years, anticancer agents have been derived from plants and currently used to treat different types of cancers in clinical practice.Thorough investigation of cytotoxic compounds in plants previously used in traditional cancer phytotherapy led to the discovery of anticancer drugs and lead compounds.For example, the chemical structure of cytotoxic phytocompound podophyllotoxin was first elucidated in 1932 (Jones 2014), followed by the discovery of the vinca alkaloids (vinblastine and vincristine) in Catharanthus roseus in 1958 (Sottomayor and RosBarcelo 2006).This was ensued by the identification of paclitaxel in 1971 (Barbuti and Chen 2015).Such molecules of plant origin have revolutionized cancer treatment, but more lead compounds need to be discovered as cancer cells are rapidly evolving and developing resistance to these drugs.It is argued therefore that novel therapeutic molecules will be developed from medicinal plants in close association with leads furnished by traditional knowledge and experiences (Omara et al. 2021c).
In the East African botanical plate, Kenya is known as one of the richest countries with diverse ethnic groups utilizing medicinal plants (Omara 2020).A recent review (Jaleny 2020) gave an overview of the herbal remedies for cancer used across rural Kenya.This study expands on the list through a comprehensive literature search exploring the ethnobotanical knowledge, phytochemistry and antiproliferative activities of plants used in the management of various types of cancer in Kenya, East Africa.

Inventory of plants used in the management of cancer in Kenya
The electronic search identified 24 reports with information on ethnomedicinal plants used in Kenya for preparation of herbal remedies for treatment of prostate, blood, bone, breast, colorectal, colon, oesophageal, lung, liver, skin, stomach, throat, uterine cancers and squamous cell carcinoma of the gum (Table 1).These sources reported a total of 145 botanical species claimed in traditional management of cancer in Kenya.The identified species were from 125 genera, spread across 55 families.Fabaceae (19 species, 13.1%), Asteraceae (11 species, 7.6%), Euphorbiaceae (8 species, 5.5%) and Rutaceae (7 species, 4.8%) were the most represented families (Fig. 1).Plant species from these families have been previously indicated for use in traditional treatment of different malignancies in other countries (Abu-Darwish and Efferth 2018;Ayele 2018;Bourhia et al. 2019;Kuruppu et al. 2019).
The study identified more 89 plant species (from 19 botanical families), adding onto the 55 species identified in the review by Jaleny (2020).This could be attributed to more studies reporting on ethnomedicinal plants usage in Kenya since the last review, and also the differences in the choice of the electronic databases used in the previous study and the current study.The most cited species encountered are Prunus africana (12 times), Launaea cornuta (4 times), Tabernaemontana stapfiana, Maytenus obscura, Flueggea virosa and Moringa oleifera (3 times each).Interestingly, some of the species recorded such as Zanthoxylum chalybeum are used in Tanzania (Matata et al. 2018), Uganda (Omara et al. 2020) and Ethiopia (Tuasha et al. 2019) for the management of cancers.The identified plants are trees (63 species, 43.4%), shrubs and herbs (40 species each, 27.6%) or climbers (2 species, 1.4%).For anticancer herbal remedies, leaves (27.3%), roots (19.0%) and stem bark (12.2%) are the most commonly used (Fig. 2).The different plant parts are used for preparation of poultices (30%), decoctions (21%) and infusions (20%) as shown in Fig. 3.However, reproductive structures such as seeds, fruits and bulbs are less commonly used, similar to reports from other countries (Omara et al. 2020).In some use reports, the plant parts used were not specified and this may be explained by the top secrecy associated with herbal medicine use in Kenya (Kuria et al. 2001;Omara 2020).

Phytochemistry and antiproliferative activities of anticancer plants reported in Kenya
Many plant species have been claimed in folklore to possess anticancer properties, and some important anticancer molecules and drugs have been isolated from such plants.For example, Camptotheca acuminata elicited antiproliferative activity against rectal, brain, liver, gastrointestinal and breast tumors and this led to the isolation of Camptothecin, an anticancer drug (Kaur et al. 2011).In Kenya, the pioneer institution in cancer research is the Center for Traditional Medicine Research (CTMDR) of the Kenya Medical Research Institute (KEMRI), Nairobi, Kenya.To date, at least 20 species of Kenyan anticancer herbal plants have been studied extensively in the laboratory, but there is little move from bench-scale experiments to product development due to underfunding by the government (Gathura 2019).Herbal anticancer products derived from Prunus africana: Tadenan, Prostafx and Pygenil are widely traded in Kenya and the East African region (Nyamai et al. 2015;Omara et al. 2020).
A review of the identified plants used for treatment of malignancies that have been reported to possess antiproliferative activities was undertaken.The most studied anticancer plants included Toddalia asiatica, Annona muricata, Carica papaya, Catharanthus roseus, Moringa oleifera, Ocimum gratissimum, Prunus africana and Zanthoxylum paracanthum (Table 2) and have various compounds reported in them (Fig. 4).However, some of the most utilized plant species such as Tabernaemontana stapfiana and Flueggea virosa have hardly been studied or have given conflicting results.For example, some potentially bioactive compounds isolated from Flueggea virosa (fluevirines E and F) elicited no appreciable antiproliferative effect against human cancer cell lines: SW480, A549, SMMC-7721, HL-60 and MCF-7 (Yang et al. 2020).
Phytochemicals elicit anticancer activity through various pathways such as inducing cleavages that yield reactive oxygen species (thereby inducing oxidative stress), inducing apoptosis, reducing cell proliferation through cell cycle arrest, inhibiting angiogenesis and tissue invasion of the tumor and cancer metastasis (Lichota and Gwozdzinski 2018).For example,
Fruit extracts increased the sub-G1 phase (apoptosis) population in HCT116 human colon cancer cells (Guon and Chung 2016) Markhamia lutea (Benth) K. Schum Cycloartane triterpenoids, musambins A-C and their 3-Oxyloside derivatives musambiosides A-C (Lacroix et al. 2011) (Nyamai et al. 2015;Ochwang'i et al. 2014).Growth inhibition of a human prostate cancer cell line (PC-3) and epithelial cells derived from a lymph-node carcinoma of the prostate (LNCaP) by 50% at 2.5 μL/mL and also induced significant apoptosis in both cell lines (PC-3 and LNCaP) at 2.5 μL/mL compared to untreated cells.Ethanolic extract had an antimitogenic effect on prostate cancer cells by inhibiting the mitogenic action of epidermal growth factor which resulted in a decreased number of cells entering the S-phase of the cell cycle (Margalef et al. 2003)   β-amyrin and β-sitosterol-3-O-glucoside from Prunus africana elicited anticancer activity against Caco-2 cell line through induction of apoptosis (Chepkoech 2014).
In addition, some of the compounds demonstrate different mechanisms of anticancer action contingent on their doses.For example, the Catharanthus alkaloids at low concentrations (< 1 µmol) inhibit microtubule dynamics and stabilize them, while at high concentrations (> 1-2 µmol), they disintegrate the microtubules and damage the mitotic spindle, triggering apoptosis by inhibition of mitosis (Lee et al. 2015).Other than the isolated compounds, it is important to note that various compounds that may be present in a plant extract can synergistically induce anticancer activity through the different mechanistic pathways.Clinical trials utilizing standardized extracts or compounds from anticancer plants reported in Kenya are yet to be done.However, extracts and compounds from species such as Catharanthus roseus and Prunus africana have previously been subjected to clinical trials in other countries (Grace et al. 2003;Kumar et al. 2013).Thus, there is need to investigate the anticancer activity of the unstudied species identified in Kenya, along with phytochemical analysis and elucidation of their mechanism of action.This review emphasizes the need for increased budgetary allocation for investigation of Kenyan anticancer plants from laboratories to clinical trials.

Study limitations
The current review had the following limitations: (1) direct studies pertaining to toxicity of the plant extracts or the isolated cytotoxic compounds were not reviewed, (2) though major abstracting and indexing databases were used for retrieving the reports reviewed in this study, some reports may have not been encountered and therefore not included in this review.

Conclusions
Ethnobotanical knowledge on the use of herbal remedies in the management of cancer in Kenya is immense.However, investigation of bioactivity, safety aspects, anticancer molecules, pre-clinical and clinical studies are required to elucidate the mechanism of action of the compounds and confirm the potential of the unstudied species.

Fig. 4
Fig. 4 Some of the anticancer molecules reported in anticancer plants used in Kenya.The compounds numbered 1-52 correspond to the molecules mentioned in Table 2

Table 1
Ethnomedicinal plants used in the management of cancer in Kenya

Table 1 (continued) Family Local name Botanical name Part used Life form Mode of preparation (administration) Cancer treated Author (s)
2 months.Taken with Z. rubescens (RB & leaves), P. africana (Rt & SB) and H. madagascariensis (SB)

Table 2
Anticancer activity of some medicinal plant species reported in Kenya for cancer treatment

Table 2
(Guevara et al. 1999)me in Raji cells.Niazimicin delayed the formation of tumors and reduced the number of tumors in vivo(Guevara et al. 1999)