Moroccan Medicinal Plants Used to Treat Cancer: Ethnomedicinal Study and Insights into Pharmacological Evidence

Cancer is one of the major medical challenges, with an unacceptably high death toll worldwide. In Morocco, medicinal plants continue to play a pivotal therapeutic role despite the development of modern sanitation systems. In the current study, an ethnobotanical survey was carried out at the Moroccan national institute of oncology, Rabat, and we aimed at (1) establishing an exhaustive inventory of indigenous knowledge of Moroccan medicinal plants used to manage cancer and (2) confirming the reported ethnopharmacological uses through bibliometric review. An ethnobotanical survey was conducted with 291 cancer patients at the Moroccan National Institute of Oncology, Rabat, during a period of 4 months, from February to May 2019, through semistructured interviews. Ethnobotanical indices, including informant consensus factor (FIC), use report (UR), relative frequency citation (RFC), botanical family use value (FUV), fidelity level (FL), and index of agreement on remedies (IAR), were employed in data analyses. The survey revealed that 39 medicinal plants belonging to 27 botanical families and 38 genera were used to treat cancer. The most used ethnospecies were Aristolochia longa with the highest RFC value (0.096), followed by Nigella sativa, Ephedra alata, Euphorbia resinifera, and Lavandula dentata, éwith RFC values of 0.072, 0.054, 0.044, and 0.044, respectively. In regard to the plant families, Lamiaceae contributed the highest number of plants with five species (FUV = 0.034), followed by Asteraceae (4 species; FUV = 0.020), and Fabaceae (4 species; FUV = 0.020). The leaves are the most popular plant part used by the studied population against cancer; otherwise, decoction was the most commonly used method for remedy preparation and the highest FIC was noticed for uterine cancer treatment (0.86). Considering these findings, further investigations into the recorded plant species should be performed to assess phytochemical constituents and pharmaceutical benefits in order to identify their active compounds for any drug formulations.


Introduction
Cancer is one of the leading causes of death in humans [1,2]. According to the World Health Organization (WHO) and the International Agency for Research on Cancer (IARC), there were approximately 9.6 million deaths and 18.1 million new cancer cases worldwide in 2018 [3]. e estimated number of new cancer cases and deaths worldwide by 2040 is around 27.5 million and 16.3 million, respectively [4]. In Morocco in 2020, there were 59,370 new cases and 35,265 cancer deaths for both sexes and all ages. Breast cancer was the most common type of cancer in Morocco (19.8%), followed by lung (12.4%), colorectal (7.7%), prostate (7.5%), non-Hodgkin's lymphoma (4.1%), and other cancers (48.5%) [5].
To date, chemotherapy, surgery, and radiotherapy remain the most frequently employed options for cancer treatment, but their toxicity and side effects restrict their usage [6,7]. Chemotherapy and/or radiotherapy may lead to some serious complications, such as fatigue, chronic pain, oral mucositis, anorexia, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, insomnia, edema, depression/anxiety, or constipation [6,7]. ese effects are difficult to manage and can significantly affect the quality of a patient's life [2].
Furthermore, due to poverty and the high cost of biological analysis and treatment, access to this type of treatment remains limited in rural Morocco and other developing countries [6]. As a result, cancer has become one of the medical challenges that has resulted in an unacceptably high death toll in these areas [8,9]. us, there is a need to revert to homegrown solutions, such as exploring the flora of our own country, Morocco, which is part of the North African botanical block and is home to approximately 4,200 taxa, 32% (1350 taxa) of which are endemic [9].
In practice, 55% to 90% of the general population frequently reports using medicinal plants to treat Moroccan cancer patients [2]. Several ethnobotanical studies conducted in Morocco have also revealed significant traditional uses of medicinal plants for cancer management. Aboufaras et al. recently conducted a survey with 530 cancer patients at Beni Mellal's Regional Oncology Center. ey reported that Aristolochia longa L., Euphorbia resinifera Berg, and Nigella sativa L. are recommended for the treatment of a variety of cancers, including breast, cervix, lung, colorectal, oral, stomach, and bladder cancers [2].
As a result, it is critical to identify natural agents present in medicinal plants that may have the anticarcinogenic potential [1,[14][15][16][17][18]. Because ethnobotanical and ethnopharmacological surveys, including those conducted with patient interviews, are effective methods for documenting and identifying medicinal plants used in traditional pharmacopeia systems, the current study was carried out at the Moroccan National Institute of Oncology (Sidi Mohamed Ben Abdellah) to record medicinal plant species used in the management of various types of cancer and to identify the potential bioactive phytochemicals in the claimed plants as well as their potential mechanisms of action via an in-depth literature revision.

Study Area.
Morocco's Rabat-Sale-Kenitra region is in the northwest (34°02′ 00″ N, 6°50′ 00″ W) (Figure 1). It has a population of about 4,580,866 people and an area of 18,194 km 2 (2.56% of the national territory). e Tangier-Tetouan-Al-Hoceima region borders it on the north, the Fez-Meknes region on the east, the Beni Mellal-Khenifra and Casablanca-Settat regions on the south, and the Atlantic Ocean on the west [19].
e Rabat-Sale-Kenitra region concentrates the majority of the Kingdom's demographic, economic, administrative, and cultural flows.
is development is mainly due to the administrative weight of Rabat, the capital of Morocco. Its exceptional geographical position, its human resources, and its natural potential make it a platform of development and a crossroad for investment and partnership [19].
e Rabat-Sale-Kenitra region has a remarkable natural and environmental heritage with numerous sites playing a major role in the conservation of biodiversity and ecosystems. is region contains over 408 vascular plant species and subspecies from 261 genera and 62 botanical families, accounting for approximately 10% of the Moroccan vascular flora [20,21]. Remarkably, this region contains many natural reservoirs, such as the Mamora forest, which is one of the world's most important ecological reserves of Quercus suber [16].

Ethnobotanical Fieldwork.
In order to collect and document indigenous knowledge of Moroccan medicinal plants used to manage cancer, a series of ethnobotanical surveys were carried out at the Moroccan national institute of oncology, Rabat (Sidi Mohamed Ben Abdellah). e target population was 1216 cancer patients who consulted consecutively during the study period. e size of the sample was estimated using the following formula [2]: where n: Sample size; N: population size � 1216, z: zscore � 1.96; e: error margin � 5%; and p: standard deviation � 0.5. e minimum sample size estimated was 291 participants, with a confidence level of 99%. Indeed, among 1216 (N) patients, 291 (n) informants with different types of cancer were selected randomly. No special selection criteria were used in the choice of the participants. e data were collected during a period of 4 months, from February to May 2019, through semistructured interviews using the Moroccan Arabic dialect, and the time spent in each interview varied from 20 to 30 min. is survey was designed first to establish the sociodemographic features of cancer patients (name, age, gender, education level, ethnicity, place of residence, and income of participants) and the traditional remedies used in cancer treatment. In fact, the questionnaire included different ethnobotanical and ethnomedicinal information such as vernacular and scientific names; plant families; plant parts used; preparation methods; administration modes; posology; side effects; and therapeutic combinations.

Species Identification, Systematization, and Preservation.
e species taxonomic identification was undertaken based on standard Moroccan floras, including the practice flora of Morocco [22], vascular flora of Morocco, inventory and chorology [23], traditional Moroccan pharmacopeia [24], and Moroccan medicinal plants [25]

Quantitative Data Analysis.
To describe the collected ethnopharmacological information, data were first sorted in the Microsoft Excel database and arranged in use reports (UR, a citation of one plant used by one respondent). en, the one-way analysis of variance (ANOVA) was used to analyze the socio-demographic data of the patients in order to determine whether there were any significant variations between the means as well as correlations between the variables (Independent Samples T-Test, p values ≤0.05 were considered statistically significant). Ethnobotanical quantitative indices were also used to discuss our findings and to clearly indicate their novelty value compared with other ethnobotanical studies, which included the informant consensus factor (FIC), the use report (UR), the relative frequency citation (RFC), the botanical family use value (FUV), the fidelity level (FL), and the index of agreement on remedies (IAR). Moreover, principal component analysis (PCA) was performed based on the ethnobotanical indices using XLSTAT statistics version 2016 software.

Informant Consensus Factor (FIC).
e FIC shows the homogeneity of the exchange of traditional knowledge between informants concerning the use of taxa to treat various disease categories. FIC was calculated using the following formula [26]: Evidence-Based Complementary and Alternative Medicine where Nur refers to the number of usage reports for each ailment (type of cancer) and Nt is the number of species used for the same ailment. A high value (close to 1) of FIC indicated that the reported plant is primarily recognized as an anticancer agent by the informants. With (0 < FIC < 1).

Fidelity Level (FL).
e fidelity level (FL) indicates the effective effects of a given plant species against a particular ailment. FL was calculated according to Sreekeesoon & Mahomoodally [27].
where Ip is the number of informants who used a specific species for a particular type of cancer, and Lu is the total number of respondents who indicated all uses of the given species for the treatment of any cancer.

Relative Frequency Citation (RFC).
e relative citation frequency (RFC) was calculated by dividing the citation frequency (FC) by the population size (N) [28].
is index demonstrates the local relative importance of each species.

Family Importance Value (FIV).
e family importance value (FIV) shows the significance of botanical families. It was established to evaluate the biological taxonomic value of species and was calculated as follows [27]: where RFC � the use value of the species belonging to the family; Ns � the number of species in the family.

Index of Agreement on Remedies (IAR).
e index of agreement on remedies (IAR) was designed to measure the value of species for which there is consensus on more than one traditional use. Indeed, a species with a high number of citations in several cancers may rank higher than plants with more citations in any single type of cancer. is index was calculated according to the following formula [29]: With Nr, the total number of use citations for a specific plant across all use categories, and Na, the number of mentioned categories.

Ethical Statement and Consent to Participate.
is study has been carried out with the permission of the committee for ethical research of the Moroccan Poison Control and Pharmacovigilance Center and the Moroccan National Institute of Oncology, under the number 310/2019. e data was collected with respect to confidentiality, anonymity, and consent. All patients were informed about the objective of this investigation. Oral and signed consent was obtained from the study participants. is comparison allowed us to assess the originality and uniqueness of traditional uses sustained by the studied population and to report new plant citations and new medicinal practices against cancer. Furthermore, the data on the in vitro and in vivo anticancer properties of these plants, as well as the mechanisms underlying their activities, were summarized. Finally, the major chemical compounds demonstrating anticancer properties were also reviewed in this study, and ChemDraw Ultra 16.0 software was used to draw their chemical structures. e IUPAC names of the reported compounds were checked from PubChem databases (pubchem.ncbi.nlm.nih.gov).

Sociodemographic Data.
According to the age distribution (Table 1, Figure 2), 55% of respondents were between the ages of 40 and 60, followed by those between the ages of 20 and 40 (29%), and only a few informants were older than 60 years old (16%). According to our findings, people over the age of 40 were the most likely to use medicinal plants to treat various types of cancer. As a result, the difference in age and indigenous knowledge was statistically significant (P � 0.001). ese findings could be explained by the fact that older people have more knowledge about the use of medicinal plants and their benefits as a result of practical knowledge passed down from older generations [16,30].
Among the 292 patients interviewed, 54% were women and 44% were men (Table 1, Figure 2). is demonstrates that women are more familiar with traditional medicine than men because women typically care for their families using medicinal plants as herbal remedies. ese findings are consistent with those of other studies conducted in Messina, Morocco [33], Moulay Yacoub, Northeast Morocco [34], and Kinmen, Taiwan [31].
Our survey showed that most of the informants were illiterate (36%), 28% had a secondary level, 23% had a primary school education, and only 13% had a university level. ese findings show that informants with lower levels of education have more frequent contact with medicinal plants, whereas those with higher levels of education have less exposure to medicinal plants and less relevant knowledge of traditional medicine. Several studies have found that illiterate people are more interested in medicinal plants than people with higher educational levels [2,[33][34][35].
In terms of habitat, findings revealed that 60% of informants lived in rural areas, while 40% lived in urban areas. People living in rural areas are closely associated with nature because of poverty and lack of access to health facilities. ese findings are consistent with those reported in previous ethnobotanical surveys [36,37].
is study showed that 51% of informants were in an intermediate socioeconomic situation, 44% were in a low socioeconomic situation, and only 5% were in a high socioeconomic situation. ese findings are consistent with those of Benkhaira et al. [30]. is could be explained by the high cost of modern medical treatments, which creates a barrier to access and drives people to seek traditional treatments [38].

Diversity of Medicinal Plants Used to Treat Cancer.
In the present ethnopharmacological survey, 39 medicinal plants belonging to 27 botanical families and 38 genera were used to treat cancer. Ethnobotanical knowledge of the inventoried plants is mentioned in Table 2, which includes the data on botanical families, vernacular and scientific names, parts used, methods of preparation, traditional dosage, route of administration, and ethnobotanical indices. e most used ethnospecies were Aristolochia longa L. with the highest RFC value (0.096), followed by Nigella sativa L., Ephedra alata Decne, Euphorbia resinifera Berg, Lavandula dentata L., and Berberis hispanica Boiss. & Reut., with RFC values of 0.072, 0.054, 0.044, 0.044, and 0.041, respectively (Table 2, Figure 3). e highest RFC values indicated that these species had an increasing traditional interest in the local area for treating cancer. Accordingly, further investigations into these species should be performed to assess phytochemical constituents and pharmaceutical benefits in order to identify their active compounds for any drug formulations [45].
Principal component analysis (PCA) showed two top principal components (eigenvalue ≥1), accounting for 84.7% of the total variation of parameters studied. To facilitate the selection of species based on the ethnobotanical parameters studied, a biplot was created using two first principal components (F1 and F2). F1 explained 63.35% of the total variation and was strongly influenced by the FC, RFC, UR, and FL. While F2 accounted for 21.35% of the total variation and was significantly influenced by the IAR index, A. longa and N. sativa were associated positively with RFC, FC, and UR, while C. sativus was associated positively with the IAR

No Primary
Secondary University Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine 7 index ( Figure 4). ese results indicated the frequent use of A. longa and N. sativa to treat cancer by the studied population, demonstrating the relative medicinal importance of these two species in the present local area. e common use of A. longa and N. sativa was already confirmed in Moroccan traditional pharmacopeia, which showed the medicinal values of these two species against cancer as well as related diseases. To that end, efforts must be made to prioritize these species for preservation and protection, as their traditional uses may place the local people under threat due to overexploitation.
In regard to the plant families, Lamiaceae contributed the highest number of plants with five species (FUV � 0.034), followed by Asteraceae (4 species; FUV � 0.020), Fabaceae (4 species; FUV � 0.020) and Apiaceae (2 species; FUV � 0.13) as shown in Figure 5. is is consistent with our previous studies carried out in different areas in Morocco, including the Rabat-Sale-Kenitra, Fez, and Taounat regions [16,30,35], where we found the dominance of the Lamiaceae, Asteraceae, Fabaceae, and Apiaceae families. Moreover, the predominance of these plant families has also been proven in numerous ethnobotanical surveys conducted in other Moroccan regions [38,[45][46][47], as well as in other neighboring countries like Algeria [48,49] and Tunisia [50]. Furthermore, the Lamiaceae and Asteraceae families have been specifically reported in traditional medicine against cancer. Besides that, these two botanical families dominate Moroccan flora and are found throughout the country [43].
On the other hand, the Lamiaceae and Asteraceae families have been linked to a variety of pharmacological effects, including antibacterial, antifungal, antiinflammatory, antidiabetic, antiviral, antioxidant, and insecticidal properties [51][52][53][54]. ese biological properties are particularly related to their valuable chemical constituents, which have shown promising therapeutic potential [18,55].

Parts of the Medicinal Plants
Used. Different parts of plants are used as medicine to create traditional cancer treatments, including leaves, seeds, stems, fruits, flowers, rhizomes, and roots. e studied population prefers the leaves against cancer (33%), followed by aerial parts (14%), seeds (13%), whole plants (11%), roots (7%), and fruits (6%) (Figure 6). Similarly, ethnobotanical research surveys conducted in Morocco revealed that leaves were a major dominant plant part used in the preparation of traditional remedies [21,39,42,44,45]. Similar findings were reported in other international ethnobotanical studies in Ghana [56], Lebanon [57], and Turkey [58]. e common traditional use of one part over another varies depending on its active fraction. e availability, ease of harvesting, and simple uses in herbal medicine remedies may explain why leaves were preferred. Furthermore, the leaves are thought to be photosynthesis and secondary metabolite storage sites, which are involved in a variety of health-promoting effects. ey contain more phenolic compounds, alkaloids, heterosides, and essential oils. However, when compared to other plant organs such as fruits, roots, and stems, exploiting and harvesting this plant part is a relatively sustainable practice; harvesting the roots may result in the annihilation and disappearance of the plants.

Methods of Remedy Preparations.
According to the current ethnobotanical study, several methods are used for remedy preparation. Figure 7 shows that decoction is the most used method (38%) for herbal preparation against cancer at various stages of development, followed by infusion (27%), and powder (23%). Other methods, such as cataplasm (5%), maceration (5%), and fumigation (2%), are rarely used by the studied population. ese findings may be supported by the fact that decoction allows for better extraction of the most active ingredients and reduces or eliminates the toxicity of certain polyherbal prescriptions [38]. e predominance of decoction in our findings is consistent with previous research in the Rabat-Sale-Kenitra, Taounat, and Fez regions [16,30,35]. Other ethnobotanical studies in Morocco [38,42,44,45] corroborate these findings.
In terms of administration, the findings revealed that most herbal remedies are taken orally. Other modes of administration, such as inhalation and massage, were also used in some traditional recipes. ese findings have also been reported in national and international traditional pharmacopeias, indicating that the oral route is the most common and acceptable mode for patients to receive plants [39,48,49,58].

Cancer Categories and eir FIC Values.
Plants identified in this survey were used to treat nine types of cancer, which can be classified as brain, gastrointestinal, kidney, leukemia, oral, pancreatic, prostate, skin, and uterine cancer.
In this survey, plants identified were used to treat nine categories of cancer, which can be grouped into brain, gastrointestinal, kidney, leukemia, oral, pancreatic, prostate, skin, and uterine cancer. e informant consensus factor (FIC) values of the claimed plants in this survey ranged between 0.36 and 0.83 (Table 3), indicating        a lack of consensus on patients suffering from a specific type of cancer in comparison to traditional knowledge, as well as a lack of knowledge exchange among people in different areas [59]. is disparity in knowledge among the cancer patients studied may be explained by their belief that all types of cancer are the same disease. In contrast, certain cancer types, such as uterine and skin cancer, showed interesting agreement among patients regarding the use of plant species (FIC values of 0.83 and 0.6, respectively). ese highest FIC values demonstrated reasonable reliability in agreement with the use of plants against cancer.

Scientific Evidence and Mechanisms of Action of Anticancer Medicinal Plants.
In this study, the 39 identified plants against cancer have been pharmacologically validated through in vitro and in vivo studies [16,[60][61][62][63][64][65]. In Table 4, we listed the mechanisms of anticancer properties of the inventoried plants used traditionally against cancer by the studied population. ese medicinal plants have shown promising anticancer properties targeting multiple checkpoints, including angiogenesis, inflammation inhibition, cell cycle arrest, metastasis, induction of cell apoptosis, and autophagy, thanks to their valuable chemical constituents (Figure 8). A. longa is the most frequently used medicinal plant by informants to treat cancer. Indeed, aqueous extracts of A. longa have been shown to induce cell death in a dosedependent manner, resulting in cell apoptosis associated with a loss of mitochondrial membrane integrity and the upregulation of caspases-9 and -3 followed by PARP cleavage [48]. Furthermore, C. sativus ethanol extracts demonstrated promising anticancer properties in MCF-7 breast cancer cells [84]. ese extracts induced caspase-dependent apoptosis by increasing the expression of the Bax protein. Furthermore, n-hexane extracts from Retama monosperma leaves induced cell cycle arrest and extrinsic pathwaydependent apoptosis in Jurkat cells [82]. Trigonella foenum-graecum seeds inhibited angiogenesis in HepG2 cells, inducing cell cycle arrest at the G2/M phase after 12 and 48 hours of treatment, and a remarkable arrest at the G1/ S phase after 24 hours [83]. Ephedra alata is another species with anticancer potential, significantly inhibiting cell growth and migration in 4T1 breast cancer cells in a dose and timedependent manner [78].
is effect was mediated by the induction of apoptosis and caspase activation, as well as the up-regulation of reactive oxygen species (ROS) production [78]. Other Asteraceae plant species, such as Artemisia herba-alba, Chamaemelum nobile, Saussurea costus, and Dittrichia viscosa, demonstrated significant anticancer properties against various cell lines, with IC 50 values ranging from 20.07 to 168.40 g/mL [62,[70][71][72]. Artemisinin, a major naturally occurring compound found in A. herba-alba, is thought to    Evidence-Based Complementary and Alternative Medicine 13 be an effective anticancer agent. Artemisinin's anticancer activity has been linked to several molecular mechanisms, including apoptosis induction, cell cycle arrest, metastasis inhibition, and increased oxidative stress via ROS and NO production [96,97]. Plants in the Lamiaceae family, on the other hand, are distinguished by the presence of specific structures involved in the production and secretion of volatile compounds as secondary metabolites, such as thymol, carvacrol, carvone, carveol, and hinokitiol ( Figure 9). Several plants, including Lavandula dentata, Marrubium vulgare, Origanum compactum, Rosmarinus officinalis, and Salvia officinalis, contain these compounds, which are responsible for their anticancer properties. Essential oils extracted from the aerial parts of S. officinalis reduced cell viability in breast MCF7 cancer, human LNCaP prostate adenocarcinoma, and HeLa cell lines after a 48-hour incubation at concentrations of 100 and 200 g/mL [89]. Furthermore, O. compactum essential oils have high cytotoxicity against MCF-7 cells, with an IC 50 of 113.42 ± 4.6 g/mL [87].
Carvacrol has also been identified as an effective anticancer agent, inducing cell apoptosis in HepG2 cell lines via caspase activation and the mitogen-activated protein kinase Evidence-Based Complementary and Alternative Medicine (MAPK) pathway [101]. Furthermore, in vivo studies showed that carvacrol has the potential to prevent liver cancer in male Wistar albino rats induced by diethylnitrosamine [99].

Conclusions
is ethnobotanical survey revealed that the locals have extensive indigenous knowledge of the use of medicinal plants, particularly for cancer treatment.
ese valuable traditional practices reflect the rich and varied floristic patrimony of the studied area. More efforts, however, must be made to prioritize certain medicinal plants for preservation and protection, as their preferred traditional uses may endanger them due to over-exploitation. Furthermore, based on the claimed results and suggested discussions, some identified medicinal plants may have a promising role in the treatment of various types of cancer at various stages of development, including prostate, gastrointestinal, uterine, leukemia, brain, skin, oral, kidney, and pancreatic cancer. However, this medicinal value requires further clarification and should be used with caution. Further research into these plant species is needed to assess phytochemical constituents and pharmaceutical benefits in order to identify active compounds for any drug formulations. Furthermore, data on the toxicity of medicinal plants is essential for ensuring the safety of their uses as well as standardizing their accurate posology and therapeutic doses.

Data Availability
All the data supporting the findings of this study are included in this article.

Conflicts of Interest
e authors declare that there are no conflicts of interest.