Medicinal Plants Used in Traditional Management of Cancer in Uganda: A Review of Ethnobotanical Surveys, Phytochemistry, and Anticancer Studies

The burden of neoplastic diseases is a significant global health challenge accounting for thousands of deaths. In Uganda, about 32,617 cancer cases were reported in 2018, accompanied by 21,829 deaths. In a view to identify some potential anticancer plant candidates for possible drug development, the current study was designed to compile the inventory of plants with reported anticancer activity used in rural Uganda and the evidences supporting their use in cancer therapy. An electronic survey in multidisciplinary databases revealed that 29 plant species belonging to 28 genera distributed among 24 families have been reported to be used in the management of cancer in Uganda. Anticancer plants were majorly from the families Bignoniaceae (7%), Caricaceae (7%), Fabaceae (7%), Moraceae (7%), and Rutaceae (7%). Most species occur in the wild (52%), though some are cultivated (48%). The growth habit of the plants is as trees (55%) or herbs (45%). Anticancer extracts are usually prepared from leaves (29%), bark (24%), roots (21%), and fruits (13%) through decoctions (53%), as food spices (23%) or pounded to produce ointments that are applied topically (10%). Prunus africana (Hook.f.) Kalkman, Opuntia species, Albizia coriaria (Welw. ex Oliver), Daucus carota L., Cyperus alatus (Nees) F. Muell., Markhamia lutea (Benth.) K. Schum., and Oxalis corniculata L. were the most frequently encountered species. As per global reports, Allium sativum L., Annona muricata L., Carica papaya L., Moringa oleifera Lam., Opuntia species, Prunus africana (Hook.f.) Kalkman, and Catharanthus roseus (L.) G. Don. are the most studied species, with the latter having vincristine and vinblastine anticancer drugs developed from it. Prostate, cervical, breast, and skin cancers are the top traditionally treated malignancies. There is a need to isolate and evaluate the anticancer potential of the bioactive compounds in the unstudied claimed plants, such as Cyperus alatus (Nees) F. Muell., Ficus dawei Hutch., Ficus natalensis Hochst., and Lovoa trichilioides Harms, and elucidate their mechanism of anticancer activity.


Introduction
Cancer ascribes a collection of diseases triggered by the uncontrolled proliferation of malignant cells. It is a global health burden that has left anintolerable death toll worldwide. Conservative estimates indicate that cancer (of the liver, breasts, lungs, cervix uteri, stomach, and colorectal) causes about 13% of annual deaths globally [1]. In Uganda, there have been reports on cancer cases, though collected data are not usually coherent [2]. e commonest types of cancer encountered in Uganda include cervical, prostate, breast, lung, and skin cancers, Kaposi sarcoma, Burkitt's lymphoma, and cancer of the bone, eye, colon, and blood (leukemia) [3]. Between 1952 and 1953, 796 cases of cancer were reported in Uganda, 15 of which were stage IV cases of cancer of the cervix uteri [4]. e 1990s recorded Kaposi sarcoma, prostate, and oesophageal cancers among men and Kaposi sarcoma, cervical, and breast cancers among women as the most prevalent cancers in Uganda [5]. e eruption of the ill-fated virus (HIV) and the AIDS epidemic led to an unprecedented increase in the incidences of Kaposi sarcoma, squamous cell carcinoma of the conjunctiva, and non-Hodgkin's lymphoma in the penultimate year [6]. Cervical cancer, the fourth most prevalent cancer globally, subsequently registered an alarming relative frequency in Uganda, with 3, 915 new cases and 2, 275 annual deaths reported [7,8]. e situation is complicated by the fact that very few (averagely less than 10% of the 10.22 million susceptible Ugandan females) have been screened for cervical cancer [7,9]. Reluctancy to screen, stigma, lack of awareness, chronic poverty, and inadequate medical services are largely responsible for the magnitude of the cancer epidemic in Uganda [9][10][11]. us, most cancer cases registered in hospitals are usually in their advanced stages that cannot be treated optimistically [12,13].
Conventional therapies for the management of cancer have several side effects due to their lack of specificity and are limited in rural settings [20]. Further, the sturdy resistance of cancerous cells to cytotoxic and antineoplastic drugs has presented a fresh challenge, giving unsatisfactory ministration outcomes and capricious resistance to antineoplastic agents [21,22]. Coupled with the prohibitive costs, unavailability of allopathic drugs, and chronic poverty in Uganda, there is a need to fold back on home grown solutions, exploring flora and fauna [23]. Uganda, the pearl of Africa, is part of the East African botanical block and is blessed with over 6,000 plant species [24,25]. Plants are regaining shape and emerging as an integral part of the ethnomedical approach for the management of diseases in Uganda [26]. e most cathartically notable anticancer botanical species in Uganda are Prunus africana (Hook.f.) Kalkman and the periwinkle plant (Catharanthus roseus (L.) G. Don) from which antitumor drugs vinblastine and vincristine have been developed [23,27]. Over 5,000 phytochemicals such as phenolics, carotenoids, glucosinolates, terpenoids, and alkaloids from over 3,000 plant species have been reported to be key actors in cancer therapy [28][29][30]. In Uganda, anecdotal reports reveal that there exists a pool of plants utilized locally for the management of cancer [23]. Indeed, information on indigenous medicinal plants used for various maladies has been reported by preceding authors, but none of them scrutinized anticancer plants. is review seeks to obtain a list of medicinal plants reported by ethnobotanical surveys in Uganda as anticancer plants and identify the active phytochemicals in the claimed plants and the anticancer studies done on them as per global studies. Potential candidates from this review which are scantily studied will be investigated in penultimate studies.

Results and Discussion
Only articles in English and local languages were considered. After the multidisciplinary database and Google search engine result assessments, sixteen reports of interest specifically on the subject of anticancer plants in Uganda were retrieved (Table 1). e botanical names of the plants listed were vetted in botanical databases: e Plant List [47], International Plant Names Index (IPNI) [48], NCBI taxonomy browser [49], and Tropicos [50]. Where a given species was considered as distinct species in different reports, the nomenclature as per the botanical databases above took precedence in the review. e botanical families used, the plant local names (Lango, Ateso, Luganda, Rukiga, Rutoro, Lusoga, Lugisu, Ngakarimojong, and Lugbara), the life forms, part(s) used, conservation status, preparation and administration mode, and the districts where the plants were reported are captured (Table 1). On anticancer potential, species studied as per global reports, the active phytochemicals reported and tested with positive results in the plant species identified by this review are reported (Table 2; Figure 1). A brief review of other ethnomedical uses of the reported species as per Ugandan and global studies is also presented ( Table 3).

Traditional Concept of Cancer in Uganda.
From the electronic survey, it is clear that local communities in Uganda have some information about cancer. Not all Ugandans are fully aware of cancer because most information on it is disseminated through television and radio stations which not all have access to. Another striking challenge is that there is no word for cancer in any of the Ugandan local languages. us, many ignore cancer because it is not anywhere recited as a health problem in their local vocabulary [16]. To many, being diagnosed with any type of cancer is equated to receiving a death sentence [234]. Some believe that conventional treatments usually cause cancer to spread, fastening the death of victims [16]. In addition, due to the ever-changing landscape of available treatment options, most patients believe that cancer can only be cured using herbal medicine and the best way to deal with cancers is through prevention [23]. Many Ugandans assume that herbal products are safer to use than allopathic drugs. In Northern Uganda, the use of shea (Vitellaria nilotica) butter, simsim (Sesame indicum L.), and groundnut (Arachis hypogea L.) pastes as substitutes for refined cooking oil and vaseline with the belief that the latter are carcinogenic is known. Unfortunately, recent reports have pointed out that some of these food items are contaminated with mycotoxins, particularly aflatoxins which are potential carcinogens [19,235].

Anticancer Plants Used in Local Communities of Uganda.
Cancer chemoprevention which involves the inhibition or reversion of cancer through the administration of natural or synthetic agents has gained a wider audience in Uganda. Chemopreventive agents may inhibit cancer development either by limiting exposure to carcinogens (carcinogen formation inhibitors and blocking agents) or by decreasing tumor promotion or progression stages (suppressing agents) [236]. Many compounds from medicinal or dietary plants have been reported as chemopreventive agents capable of inhibiting DNA damage and retarding or reversing carcinogenesis in in vitro and in vivo bioassays [237].
Garlic derived S-allylmercaptocysteine (SAMC) suppressed the proliferation of hepatocellular carcinoma cells [66]. SAMC inhibited the proliferation of human colorectal carcinoma SW620 cells [67] Allicin inhibited the proliferation of gastric adenocarcinoma cells by inducing cell cycle arrest [68].
Ethanolic extract of the pericarp (50-640 μg/mL) inhibited the growth of breast cancer cell line (MCF-7) treated with sodium nitroprusside, a nitric oxide donor [111]. , and pancreatic adenocarcinoma cell line (Capan-1). In peripheral blood mononuclear cells, the extract reduced the production of IL-2 and IL-4 whereas it increased the production of 1 types cytokines such as IL-12p40, IL-12p70, INF-c, and TNF-∝ . e expression of 23 immunomodulatory genes was enhanced by the addition of papaya extract [114] Leaf juice not only exhibited a stronger cytotoxic effect on human squamous cell carcinoma (SCC25 cancer) cells but also produced a significant cancer-selective effect as shown by tests on noncancerous human keratinocyte HaCaT cells [115] Catharanthus roseus (L.) G. Don.
Some of the plants have been reported to have cytotoxic and antitumor properties ( Table 2) and many possess other ethnomedical applications (Table 3) both in Uganda and internationally. Interestingly, the isolation, characterization, and purification of the anticancer and cytotoxic phytoconstituents have been successfully done in some species (Figure 1). Striking examples are Prunus africana (Hook.f.) Kalkman which have been patented in France for the management of prostate cancer [245] and Catharanthus roseus (L.) G. Don from which the commercial anticancer drugs vincristine and vinblastine have been developed [246].
Phytochemicals from plants are reported to be effective against cancer cells because they have many molecular targets [247]. For example, β-sitosterol present in P. africana has been shown to exhibit anti-inflammatory, antineoplastic, and immunomodulating activities [248]. It is worth mentioning that antioxidant activities and antitumor or anticancer properties of plant extracts are always reported

Plant
Active phytochemicals Molecular targets and/or effects on cancer cells
Skimmianine, furoquinoline alkaloid skimmianine, the benzophenanthridine alkaloids chelerythrine and nitidine, the aporphine alkaloids tembetarine, magnoflorine, N-methylcorydine, N-methylisocorydine (menisperine), and berberine and the phenylethylamine candicine, alkamide, fagaramide, dihydrochelerythrine, lupeol, and sesamin [172] Extracts showed moderate cytotoxicity with IC 50 values below 50 μM against the drug-sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cell lines [172] Stem bark extracts exhibited potential cytotoxicity effect with LC 50 value of 5.74 μg/mL in brine shrimp assay [173] Cytotoxicity reported against human cancer cell line HL-60 cells with IC 50 of 137.31 μg/mL and selectivity index of 3.81 [174]. Cytotoxicity against human gingival fibroblasts cells with IC 50 of 26 ± 3 μg/mL [175] Cytotoxicity of root bark extracts reported with IC 50 of 38.5, 68.9 and < 500 μg/mL in brine shrimp toxicity assay [97,134,176] IC 50 : -median inhibitory concentration/half maximal inhibitory concentration, LC 50 : median lethal concentration, and IC 90 : concentration inhibiting 90% of cellular growth. Evidence-Based Complementary and Alternative Medicine concomitantly in several plants [166], and some studies demonstrated that there is a positive linear relationship between antioxidant activity and anticancer effect of plant extracts [249]. Plant phytochemicals such as artemisinin from the Artemisia genus are reported to have an endoperoxide moiety which is strategic for their bioactivity. e cleavage of this is reported to produce reactive oxygen species, inducing oxidative stress. Furthermore, in the presence of ferrous iron or reduced heme, artemisinin can convert itself into cytotoxic carbon-centred radical, a highly potent alkylating agent, to induce direct oxidative damage to cancer cells [250,251]. us, they are reported to induce apoptosis and ferroptosis, reduce cell proliferation through cell cycle arrest, and inhibit angiogenesis and tissue invasion of the tumor as well as cancer metastasis [184,250,251].
Treatment of stomachache, cough, fever, skin rush, diabetes [33,42,43], HIV [198], malaria, diarrhea, sickle cell, tuberculosis, pneumonia, colds, ulcers, sore throat, measles, bilharzia, amoebiasis, female sterility, uterine fibroids, and headache [226][227][228][229][230] Anticandidal, antibacterial, and antidiabetic activities [173,[231][232][233] NR: none retrieved in the open literature. 16 Evidence-Based Complementary and Alternative Medicine pounded to produce ointments that are applied topically (10%). e plants are collected from the wild, cultivated fields, or home gardens when needed. Traditional medicine practitioners either collect herbal plants personally or hire collectors. All traditional medical practitioners cultivate some medicinal plants especially fast growing ones around their homes and shrines in order to have them within easy access when needed [26]. e preparations are majorly administered orally, except in cases of skin cancers where they are applied topically as ointments.

Other Ethnomedicinal Uses and Toxicity of the Reported
Anticancer Plants. Almost all the plants recapitulated in this review are employed for the treatment of various ailments other than cancer. Albizia coriaria (Welw. ex) Oliver used in the management of venereal diseases (syphilis, HIV, and gonorrhoea), postpartum haemorrhage, sore throats, menorrhagia, threatened abortion, skin diseases, jaundice, cough, and sore eyes [33,179] is a good representative example. Such plants tend to be used in different communities for treating cancer and can be a good justification for their pharmacological efficacy [26].
On the other hand, some of the anticancer plants cited exhibit marked toxicity. A striking example is Catharanthus roseus (L.) G. Don. e alkaloids in it are neurotoxic, especially vincristine [252]. Vincristine and vinblastine are highly toxic antimitotics, blocking mitosis in metaphase after binding to the microtubules [253]. Evidently, side effects such as myelosuppression, alopecia, abdominal cramps, constipation, nausea, paralytic ileus, ulcerations of the mouth, hepatocellular damage, kidney impairment, pulmonary fibrosis, urinary retention, amenorrhoea, azoospermia, orthostatic hypotension, and hypertension [254][255][256] have been reported for the commercial drugs vincristine and vinblastine derived from this plant. In essence, the administration of these drugs must be carefully controlled to reduce the side effects [257]. is observation explains, in part, why some anticancer preparations in Uganda are applied topically or ingested in small amounts. Fortuitously, topical application is a better approach for reducing the local action of cancer cells at externally affected parts.  [245,246]. Prostafx, Tadenan, and Pygenil are some of the herbal preparations of Prunus africana (Hook.f.) Kalkman on the market. Due to the paucity of data generated from preclinical tests (pharmacokinetic and toxicological studies) and the regulatory requirements for clinical studies, the safety and efficacy of traditional anticancer plant preparations used in Uganda remain a secret yet to be unveiled. Although there are many research institutes such as Uganda Virus Research Institute, Natural Chemotherapeutic Research Institute, Uganda Industrial Research Institute, and National Agricultural Research Institute, none is designed to have an in-depth focus on drug discovery and development to the level of commercialization. us, the government of Uganda should establish an institute that handles drug discovery and development to enhance the utilization of medicinal plants in Uganda.

Conclusions and Recommendations
e inventory of plants utilized by Ugandan communities presents considerable potential for the treatment of cancer. Cyperus alatus (Nees) F. Muell, Ficus dawei Hutch, Ficus natalensis Hochst, and Lovoa trichilioides Harms are some of the plants with claimed anticancer potential that have been hardly studied and therefore warrant further investigations. More ethnobotanical surveys should be done in the unsurveyed districts to identify other potential anticancer plants. Albizia coriaria Welw. ex Oliver which doubles as an antivenin plant will be investigated for its anticancer potential in a penultimate study.

Disclosure
Timothy Omara and Sarah Kagoya are co-first authors.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors' Contributions
Timothy Omara and Sarah Kagoya contributed equally.