Phytodentistry in Africa: prospects for head and neck cancers

Healing with plants is as old as mankind itself. The link between man and his quest for treatments in nature dates back to ancient times when anecdotal evidence was garnered from monuments, written documents, and even original plant medicines [1]. Plants have been used for prophylaxis and healing of diverse diseases before the advent of iatrochemistry in the sixteenth century [2]. This has been particularly showcased in Africa since ancient times, with the widespread integration of medicinal plants in the indigenous healthcare practices.

Africa is known as the cradle of mankind and it possess a rich cultural and biological diversity [3]. Phytopharmacology and phytomedicine has been in Africa for centuries and is considered the most widely used method for healing practices. Phytomedicine in Africa employs a holistic approach which considers both the healing of the mind and the body. The psychological basis of diseases is first addressed before medical regimens (typically-derived) are provided to cure the disease [4]. There are 3 major reasons why there is a sustained interest in African phytomedicine, viz: poor access to western allopathic medicines due to lack of financial resources, manpower and health infrastructure; lack of efficacious modern medicine for some illnesses which are typical to Africa; and the rich diversity of the African flora and fauna [5]. In addition, detrimental side effects and reducing efficacy of synthetic western drug have re-awakened the attention of researchers globally to natural medicine (particularly from Africa), in recent times [6]. Such efforts have revealed a plethora of African plants that have potent pharmacological effects and hence are good candidates for the development of lead compounds in the drug discovery pipelines.

Phytomedicine is globally sought after as a means primary healthcare provision for ca. 3.5–4.0 billion people, and a significant percentage of this involves the use of plant-derived decoction and medicines [7]. More so, using medicinal plants has been the most commonly practised traditional medicine system across the African continent. Medicinal plants are readily accessible health resources for many African communities [8]; and they are often more preferred over conventional medicine [9]. Information, treatment and counselling, garnered from traditional healers are presented to patients and their families in a more indigenous and cultural manner [10]. As a matter of fact, Africa is highly endowed with plant biodiversity constituted by ca. 40,000 to 45,000 plant species that can be potentially developed; and close to 5000 of these are currently medically applied according to pharmacopoeia information [11, 12]. The fact that Africa is situated tropically with subtropical climate favours an adaptive accumulation of secondary plant metabolites [13]. Strong ultraviolet rays from tropical sunlight and pathogenic microbes, such as fungi, bacteria, and viruses are additional factors that promote the accumulation of plant chemopreventive in relatively higher concentrations compared to northern hemisphere flora. A Dorstenia (Moraceae) study reported Dorstenia mannii Hook.f, which is perennial to the tropical central African rain forest to contain more biologically active components as compared to other related species [14].

Hence, accurate documentation of indigenous African plant medicinal systems has become essential, to mitigate the continuous erosional and anthropogenic loss of natural habitats. It has been reported that even though Africa has close to 216 million hectares of forest, she unfortunately also has one of the highest levels of deforestation globally (ca. of 1% per annum) [15]. Against this backdrop, limited healthcare resources and high burden of head and neck cancer [16] warrants a more extensive use of phytopharmacological compounds in the African dental setting. This review focuses mainly on the potential beneficial effect of medicinal plant bioactive compounds, for the management of cancers (particularly head and neck), in the context of Africa.

Nature is the most effective source of naturally occurring herbs that are a reservoir of pharmacologically active phytochemicals and phytomedicine. Their easy accessibility, affordability, safety and efficacy have hugely culminated in their success against some severe diseases and reliability among the users [17]. Indeed, conventional medicine has its roots in medicinal plants, and it is likely that many novel remedies will still be developed and commercialized in the future from the African biodiversity, as it has been till now, by following the leads provided by traditional knowledge and experiences [4, 12]. Over the last decade in Africa, there has been enormous rise in medicinal plants-derived products in terms of interest and use [10]. Prior to this time, what used to be the exclusive domain of health food and speciality stores has now gained considerable popularity into the mainstream market as evident by their impressive sale at some of the major retail outlets, their publicity, and advertising in the media, and due to the entry of various pharmaceutical giants in the area of phytomedicines. Also, despite that dosage standardization, exact mechanism of action and safety issues could still be identified as factors militating against the use of many of the medicinal plants within the African setting and beyond, the World Health Organization (WHO, 2000) has encouraged African member states to promote and integrate traditional medical practices in their health system.

Unlike the first and second generation phytopharmacological advancements in Africa, the third and indeed the current generation is poised to encourage formulations based on well-controlled double-blind clinical and toxicological studies to improve the quality, stability, safety and efficacy of such formulations [8]. Also, contrary to the argument that appreciation of phytomedicine in Africa is linked to cultural and economic reasons, emerging evidence from clinical and experimental data strongly suggests their therapeutic efficacy against several diseases including diabetes, malaria, sickle-cell anaemia, Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), cancer, dental disease, stroke, ulceration, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and microbial infections etc. [6, 10, 15, 18‐23]. Furthermore, through appreciation of phytopharmacology, many African phytomedicines have become well known in the international markets and several of them including a Cameroonian plant (Ancistrocladus abbreivatus) with anti-HIV/AIDS potential, Elaeis guineensis, Agava sisalana, Tamarindus indica, Zingiber officinale, Capsicum annum, Phytostigma venenosum, Catharantus roseus, Rauvolfia vomitoria, Chrysanthemum cinerariifolium, and Prunus africana etc. with diverse pharmacological activities are exported to other parts of the world and contributing to the economic development of the region [8].

In spite of the tremendous efforts of African phytopharmacologists to decipher African ailments and proffer lasting solutions, gaps still exist and there is a need for a more holistic, rational, and generally acceptable strategy to explain the efficacy of medicinal plants and their mechanisms of action. In view of this, the concept of “-omics” (metabolomics, proteomics, transcriptomics, and genomics etc.) as currently being explored, could find relevance and may provide useful data supporting the efficacy of phytotherapy. Ultimately, this will annihilate the mainstream issues against the advancement of phytopharmacology in Africa and making it one of the focal contributors to research advancement and economic development of the continent. Research in this direction holds promising scope for discovering precise and novel therapeutic products in Africa and beyond.

Over the years, cancer continues to impose a heavy burden on public health and presents a challenge to science. Globally, cancer is a leading cause of death; it is believed that the growth and aging of the population will increase cancer burden, especially in Africa, Asia, Central and South American, where approximately 70% of the world’s population resides [24, 25]. This disease has been labelled as a global menace and kills more people than AIDS, tuberculosis and malaria combined [26, 27]. As documented by Ferlay et al., [25], head and neck cancer accounts for over 600,000 cases yearly, with 40%–50% mortality. In fact, over half of all sufferers will eventually die of the disease [28]. The tumours arise in the epithelial cells of the mucosal linings of the oral cavity, nasal cavity, oropharynx, pharynx and larynx, most of which are squamous cell carcinoma of the head and neck (SCCHN) [29]. In addition to the synergistic effect of tobacco and alcohol, which is the most important risk factors for SCCHN, infection with human papillomavirus (HPV) has also been implicated in the pathogenesis of SCCHN [30]. Besides these exogenous risk factors, Fanconi anaemia and a more general genetic susceptibility may cause SCCHN [30, 31]. The choice of treatment of SCCHN is largely dependent on the stage and location of tumour. The stage of the tumour is determined by the extent of the tumour, presence of lymph node metastases and distant metastases. More so, correct staging with the aid of computed tomography (CT) or magnetic resonance imaging (MRI) by a head and neck surgeon is of paramount importance in therapeutic decision making [29]. Current treatment options include surgery and radiotherapy. However, recurrent and metastatic cancer is generally untreatable. As reviewed by Forastiere et al [32], great strides have been made in the treatment of head and neck cancer, but existing treatment options are still faced with one or more challenges. Noteworthy is the invasiveness of surgical methods and chemotherapeutic agents toxicity; both usually accompanied with severe side effect on non-target cells. Certainly, there is an unmet need for development or exploration of alternative and complementary treatment options. Based on extensive literature search, it could be opined that the use of monotherapy and surgery, as often the case, might not be exhaustive and efficacious treatment for cancer. Consequently, an important area researchers and clinicians should focus SCCHN investigations into is the application of phytopharmacology in managing, curing or ameliorating treatment-induced toxic effects.

Medicinal plants are made up of various chemical constitutes that works independently, supplement or in synergy to improve health [3]. These natural plant-derived medicines that have been used in the remedy of various health problems, have a safe profile, they are gentle, cost-effective and easily accessible; and this has encouraged self-medication without consulting a medical practitioner [33‐36].

While the exact molecular mechanisms by which medicinal plants mediate their chemo-preventive (cancer preventive) properties are still unclear, it has been suggested that the mechanism of medicinal plant-derived chemo-prevention may be due to the presence of phytocompounds (which may work in a synergistic/combinatorial manner) with strong antioxidant and antiproliferative properties [37]. Similarly, it has been reported that the chemical constituents of medicinal plants can induce apoptosis, possess anti-inflammatory, anti-hormonal and immune-enhancing effect. They can also induce cell cycle arrest, cell differentiation, suppression of cellular proliferation and angiogenesis; as well as inhibiting secondary modification and development of the neoplastic cells [38].

It has been suggested that phytocompounds can carry out their antioxidant activities by lowering free radical production through metal chelation and free radical scavenging [22, 39]. In addition, phytocompounds can reduce mitochondrial damage and fission, thereby enhancing the electron transport chain and oxidative phosphorylation [39]. The transcription factor nuclear erythroid 2-related factor 2 (Nrf2) can be activated and translocated to the nucleus, by polyphenols (e.g., hydroxytyrosol), where it can transactivate antioxidant enzymes and phase II genes, by binding antioxidant response elements promoters [38, 39]. Anti-inflammatory effect of phytocompounds have been linked to downmodulation of proinflammatory cytokines, prostaglandins, NF-κB, nitric oxides, as well as inducible NO synthase (iNOS) and other pro-inflammatory genes [39]. Furthermore, hydroxytyrosol has been found to influence cellular energetics by increasing the expression of respiratory chain mitochondrial complexes (I-V) and overall mitochondrial function [39].

The understanding of the structure and function of proteins is an important phenomenon in deciphering the molecular basis of diseases. Hence, structural biology is a research field of study that focuses on determining the function, molecular mechanisms and structure of biological molecules or proteins. The field has aided the understanding of basic molecular mechanisms in diseases such as designing of new pharmaceutical products, as well as understand drug action [68, 69]. Thus, structural phytopharmacology is an approach used in designing and developing novel drugs to target and inhibit proteins or biological molecules through the means of medicinal plants and their products.

Cost and unavailability of orthodox drugs and health care, as well as several side effects associated with the use of synthetic drugs, makes using phytocompounds a potentially valuable and practical options [70]. Therefore, the exploration of pharmacologically active substances found in plants has been a better alternative in medical applications, this is due to the presence of several complex chemical substances of diverse composition which are found as secondary metabolites (phytonutrients or phytochemicals) such as flavonoids, terpenoids, alkaloids, saponins, polyphenols, lignans, carotenoids, indoles, isoflavones among others [71]. Globally, functional bioactive compounds (FBCs) of plants source or plant-derived compounds have been significant sources of therapeutic drugs for humans and animals in treatment of diverse diseases [72]. FBCs possess numerous chemical and structural properties such as the ability to interact or binds and stimulate a specific molecular receptor or protein and this has led to several important discoveries. For instance, gingerol, resveratrol, phytosterol, epigallocatechin, myricetin, among others may directly influence several molecular signal transduction pathways such as cell migration/proliferation, metabolic disorders, inflammation cascade, and oxidative stress which are implicated in the development of different non-communicable diseases [73‐75], such as cancer.

The use of medicinal plants in the treatment of diseases (ethnomedicine) is an ancient tradition that has co-existed with human habitation [84]. Overall, several phytocompounds have been demonstrated to be of therapeutic importance, but fewer numbers have been brought into clinical dental utility (Fig. 1). Persistent rise in the incidence of oral cancer has long been recognised as a major public health problem worldwide [85], and locally in Africa [16]. Phyto-constituents derived from medicinal plants have proven to be an important source of therapeutically useful compounds with the potential of being developed into new and potent pharmaceuticals [85]. Phyto-dentistry, the use of plants and their products in dental practice has long been documented, however, plant products have only been marginally used in dental material, as well as an adjunct therapy in dental practice [84]. Emerging omics fields and development of state-of-the-art omics instrumentation is expected to accelerate the uptake and application of phytodentistry to treating head and neck cancers, and indeed other dental diseases. Hence, this review heralds a wider coverage of phytodentistry for improved, personalized and cost-effective treatment of dental diseases in Africa.