Anticancer effect of Moringa oleifera in oral squamous cell carcinoma: a systematic review

Abstract

Background and objective

Oral squamous cell carcinoma is the most common form of mouth cancer. As plant-based medicines become increasingly popular, Moringa oleifera has been studied extensively for its plant-based components, and health benefits. The present review examined the anticancer effects of Moringa oleifera extracts on Oral squamous cell carcinoma.

Materials and methods

The study complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. A comprehensive search was performed on PubMed, Scopus, and Google Scholar to find research papers published from January 2015 to August 2024 that assessed the effects of extracts of various parts of Moringa oleifera in Oral squamous cell carcinoma. Two independent reviewers separately assessed research study titles, abstracts, and the chosen full-text papers. The risk of bias in non-randomized exposure studies was classified as low, with some concerns high and extremely high.

Results

The final review yielded four in-vitro investigations, two molecular analyses, and five animal models. The study revealed that Moringa oleifera plant components have antioxidant, anti-inflammatory, anticancer, and chemo-preventive properties. All the 11 studies showed a low risk of bias.

Conclusion

The studies reviewed herein reveal that Moringa oleifera plant components have antioxidant, anti-inflammatory, anticancer, and chemopreventive properties. Although more clinical trials are needed to fully establish its efficacy and safety as a complementary therapy, the growing body of evidence positions Moringa oleifera as a promising natural adjunct to cancer treatment strategies.

Introduction

According to GLOBOCAN estimates (2020), HNSCC is the seventh most common cancer globally, accounting for an estimated 890,000 new cases (roughly 4.5% of all cancer diagnoses around the world) and 450,000 deaths per year (roughly 4.6% of global cancer deaths). Oral squamous cell carcinoma (OSCC) is the seventh most prevalent cancer worldwide, constituting about 4.5% of all cancer diagnoses globally. Moreover, it leads to around 450,000 deaths annually, representing approximately 4.6% of global cancer-related deaths. Globally, OSCC is more prevalent in men than in women, and it is more common in adults over 50 years of age [1].

OSCC is the most generally known oral malignant condition in India and the world's sixth most prevalent cancer. Contemporary cancer treatment options include chemotherapy, surgery, radiotherapy, targeted treatment, adjuvant therapy, and immunotherapy. However, these strategies did not deliver the anticipated outcomes and instead resulted in undesirable effects such as nausea, vomiting, fever, and tumour site pain [2]. Consequently, there is always a need for innovative and potent phytochemicals with less toxicity and adverse effects [3]. These indigenous bioactive substances such as flavonoids and polyphenols, can lower the incidence of OSCC since they include an extensive amount of phytochemicals with anticancer activities. Thus, medicinal herbs can be utilized to alleviate and manage OSCC [4].

Moringa oleifera has shown promising potential in cancer research, including its effects on OSCC. Extracts from Moringa, particularly its leaves and seeds, contain bioactive compounds like quercetin and kaempferol, which have demonstrated anti-cancer properties [5, 6]. Studies suggest that Moringa extracts can inhibit the proliferation of cancer cells, induce apoptosis (programmed cell death), and reduce oxidative stress, which plays a significant role in cancer development. In the context of oral squamous cell carcinoma, research indicates that Moringa oleifera’s bioactive substances in MO react with OSCC cell lines and exhibit antiproliferative action, akin to several anti-cancer medications Moringa continues to attract attention for its potential use as a complementary therapy in oral cancer due to its rich phytochemical profile [7].

MO is widely utilized in conventional medical practices around the globe [8]. It is utilized in ayurvedic treatment and is thought to be effective in averting 300 ailments [9]. MO leaf contains high levels of phenolics and glucosinolates, tocopherols, carotenoids, polyunsaturated fatty acids, minerals, and vitamins. Studies also demonstrated that MO leaves contain 35 compounds [10, 11]. It is utilized for a variety of purposes, including purifying the blood and liver, enhancing cardiac function, deworming, and improving fat metabolism to aid in weight reduction [12]. Various components of the MO are believed to have antidiabetic, anticancer, anti-inflammatory, antispasmodic, antihypertensive, reducing cholesterol, antioxidant, hepatoprotective, antimicrobial, and antifungal properties [13]. Various research has investigated the anticancer properties of the leaves, fruits, flowers, stems, and roots of MO [7, 14, 15]. The anti-carcinogenic efficacy of MO is attributed to niazimicin, quercetin, niazinin, glycerol-1(9-octadecanoate, and (4(a-l-rhamnosyloxy) benzyl) carbamate [16]. The current review evaluated the antiproliferative and cytotoxic effects of extracts from various parts of MO against OSCC.

Materials and methods

Study protocol

The study adhered to the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for the selection of studies, synthesis of data, and eventual dissemination of results [17, 18].

This systematic review has been duly recorded in the PROSPERO database (CRD42024588129).

Focused question

The research question was “Do the extracts of Moringa oleifera possess anticancer properties for the management of Oral squamous cell carcinoma?".

Information sources and search strategies

We conducted a comprehensive search on PubMed, Scopus, Cochrane, and Google Scholar to find research papers published from January 2015 to August 2024 that assessed the effects of extracts of various parts of MO in OSCC. After conducting a thorough examination of the available literature, the following combination of Medical Subject Headings (MeSH) phrases was used: (“Moringa oleifera” OR “Leaf extract” OR “Seed oil extract” OR “Phytochemicals” OR “Plant-based compounds”) AND (“Oral squamous cell carcinoma” OR “Oral cancer” OR “Head and neck cancer”) AND (“Antioxidant” OR “Anti-inflammatory” OR “Anticancer” OR “Chemopreventive” OR “Antiproliferative” OR “Apoptosis” OR “Cytotoxic” OR “Anti-angiogenesis” OR “VEGF expression” OR “Caspase expression” AND “Mass spectrometry” OR “MTT assay” OR “DPPH scavenging capacity” OR “Immunohistochemistry” OR “FRAP assay”). To identify articles that were not available in digital databases, a comprehensive examination of the references from the studies chosen was conducted. Two reviewers conducted an impartial search and evaluated the records according to the prerequisites of the review.

Eligibility criteria

Inclusion criteria:

1. Studies reported on OSCC with Moringa oleifera.

2. Randomized clinical trials and analytical studies.

3. In-vitro and Animal studies.

4. Studies published only in the English language.

Exclusion criteria:

1. Case reports and case series.

2. Studies not including survival of patients.

3. Narrative reviews and pilot studies.

Study selection

Articles that failed to comply with the standards were eliminated. Two independent reviewers assessed research study titles, abstracts, and the chosen full-text papers separately. In the absence of a consensus, a third reviewer was asked to conclude, and all three evaluators agreed unanimously.

Data extraction

A planned data collecting technique was employed for gathering data such as the first author and journal, study title, year of publication, place of study, study design, type of cell lines, animal models, phytoextracts of MO utilized, anticancer effects, laboratory assays employed and study inference (Table 1).

Table 1. Characteristic traits of the reviewed studies

Author-year	Country	Type of cell line/animal model	Major effect studied	Type of MO extract	Laboratory assays	Study inference
Budhy et al. 2024 [24]	Indonesia	Male Wistar rats (Rattus norvegicus)	Expression of tumour necrosis factor α (TNF-α), heat shock protein (HSP27), and interleukin-10	MO leaf extract nanoparticles	Immunohistochemistry	MO leaf extract showed significant differences in IL-10 expression between control and treatment groups, with the highest expression in the 500 μg/mL group, suggesting its potential as a plant-based ingredient for treating OC
Das et al. 2024 [19]	India	CAL27 and SCC15	Anti-proliferative and cytotoxic effect	MO seed oil extract	MTT assay, Mass spectrometry	With increasing oil dose, cell viability decreased significantly, demonstrating MO seed oil's cytotoxic and anti-proliferative action on OC cell lines
Kumari et al. 2024 [23]	India	Human PARK2 protein structure	PARK2 regulated OC regulation	Bioactive compounds such as kaempferol, niazimicin, niazinin, O-ethyl-4-(alpha-l-rhamnosyloxy) benzyl carbamate and quercetin of MO	In silico study	The study revealed Kaempferol's therapeutic development potential in the context of PARK2-related OC control
Syahputri et al. 2023 [25]	Indonesia	Rattus norvegicus	Anti-angiogenesis	MO leaf extract	Immunohistochemical analysis	The optimal dose of MO extract to suppress OC cell angiogenesis in rats generated by benzo(a)pyrene was 40 mg/kg body weight
Pertami et al. 2021 [26]	Indonesia	25 Rattus norvegicus Wistar strain	Caspase 3 expressions	Dried MO leaves	Immunohistochemistry	MO leaves extract at 9.375% might enhance OSCC Caspase 3 production
Rath et al. 2021 [4]	India	Protein structure of P53	Apoptosis pathway	Eight bioactive compounds from MO	Molecular docking	The study found that quercetin docks effectively with targeted p53, while other chemicals have lower affinity
El-Hussieny et al. 2020 [24]	Egypt	Hep-2 cells	Cytotoxic and apoptotic effect	MO leaf extract	MTT, ELISA, Nuclear area factor (NAF) assays	In addition to reducing proliferation, MO extract and cisplatin increased caspase 3 expression, apoptotic morphological alterations, and NAF values, indicating apoptosis in Hep-2 cells
Luetragoon et al. 2020 [21]	Thailand	Human monocyte-derived macrophages, and SCC15	Apoptosis	MO leaf extracts and their fractions, 3-hydroxy-β-ionone (3-HBI)	MTT assay, immunoblotting	MO extracts and 3-HBI inhibited SCC15 development and induced apoptosis
Syahputri et al. 2020 [27]	Indonesia	25 male Wistar rats	Heat shock factor 1 (HSF1) expression induced by benzo[a]pyrene	MO leaf extract	Immunohistochemical staining	Ethanolic extract of MO leaves at 3.125%, 6.25%, and 9.375% can reduce benzo[a]pyrene-induced HSF1 production in OC
Wang et al. 2020 [22]	China	HNC cell lines, CNE-1 and CAL27	antioxidant and anti-proliferative	MO extracts from seeds, roots, stems, and leaves	DPPH scavenging capacity, Colony formation assay, apoptosis analysis, Western blot, DAPI nucleus staining, ABTS. + scavenging ability, FRAP assay	Stem MO extract induced apoptosis the most, followed by leaf extract. These findings suggested that MO extracts may mitigate the effects of HNC due to their antioxidant properties
Hartono et al. 2019 [28]	Indonesia	Wistar rats	VEGF expression	MO leaf extract	Immunohistochemical staining	MO leaf extract at 3.125% reduced oral cancer cell VEGF production significantly in Wistar rats

MOMoringa oleifera Lam., OC oral cancer, HNC head and neck cancer

Quality assessment

The ROBINS-E was classified as low, with some concerns, high, and extremely high [18]. The instrument assesses confounding, exposure measurement, selection, post-exposure treatments, missing data, evaluation of outcomes, and selective reporting bias.

Results

As illustrated in Fig. 1, the informational repository and manually conducted searches yielded 313 references. After deleting duplicate materials and categorizing articles according to the requirements for eligibility, the review included four in-vitro investigations [19–22], two molecular studies [4, 23], and five animal models [24–28] (Table 1).

Fig. 1 [Images not available. See PDF.]

PRISMA (2020) flow chart of the reviewed studies

Quality assessment of evaluated studies

All of the studies that were analyzed showed a low RoB when evaluated using the ROBINS-E technique, except for one study [19] (Fig. 2). The ROBINS-E across the analyzed studies is illustrated in Fig. 3.

Fig. 2 [Images not available. See PDF.]

ROBINS-E tool for determining the risk of bias within each of the reviewed studies

Fig. 3 [Images not available. See PDF.]

ROBINS-E tool for determining the risk of bias across the reviewed studies

Discussion

Several investigations have also documented comparable results, particularly studies focused on the mechanisms by which the MO leaf extract (MOLE) induces tumour cell apoptosis. Multiple investigations have documented that the MOLE induces a higher production of reactive oxygen species (ROS), which in turn causes DNA fragmentation, leading to apoptosis. El-Hussieny et al., observed comparable results of increased caspase 3 production and apoptotic structural alterations, alongside a drop in average nuclear area factor readings. MO demonstrated a detrimental impact on the growth of Hep-2 cells by inducing programmed cell death by the activation of caspase 3, a hallmark of apoptosis [20] Das et al. [19] reported good dose-dependent effectiveness in their MTT assay. CAL27 and SCC15 cell lines demonstrated a substantial decline in cell survival after 24 h, with IC50 values of 17.78 µg/mL and 24.28 µg/mL for each of the groups treated with MO, respectively. Wang et al. [22] found that aqueous extracts had the most antioxidant activity in leaves, while 70% ethanol extracts exhibited the best effect in the stems, roots, and seeds of MO. In addition, MO extracts had shown strong anti-cancer activity against head and neck cancerous cells.

Abd-Rabou et al. [29, 30] observed that the nanoformulation of MO seed oil extract induced more cytotoxicity in colorectal cancer cells through mitochondrial breakdown in comparison to the free form of MO. Conversely, MO nanoformulations and MO effectively trigger mitochondrial apoptosis in HCT 116 cells, while causing insignificant harm to normal BHK-21 cells. TNF-α and HSP27 levels varied considerably across control and treatment groups, with the 125 μg/mL treatment group exhibiting the highest levels. IL-10 expression differed considerably across control and treatment groups, with the most elevated levels found in the group receiving a concentration of 500 μg/mL [24]

Immunohistochemical examination was utilized to measure IL-8 expression, and the data analysis showed that the 40 mg/kg body weight had the least level of IL-8 production in the endothelial cells of the animal model that was cancer-induced by benzo(a)pyrene [25] The MOLE can control the production of Caspase3, VEGF, and HSF1 in rodents with OSCC. Caspase-3 is a caspase executor that can be induced directly from caspases 8 and 9. The activated caspase ultimately leads to DNA fragmentation, resulting in apoptosis in cancerous cells. The Rattus norvegicus groups receiving MOLE at 3.125% and 6.25% were able to boost caspase-3 production in the cancer category. Still, the effect was enhanced in the group administered with MOLE at 9.375% [26].

Immunohistochemistry analysis demonstrated that heat shock factor-1 activity in the treatment groups was significantly lower than in the positive control group. Nevertheless, no significant variations were observed between the therapy groups [27]. Hartono et al. [28] reported a similar conclusion, with a substantial reduction in VEGF production in all treatment groups in comparison with the untreated controls. On the contrary, no significant change was found between the intervention groups.

Luetragoon et al. [21], documented that MO extracts of leaves and fractions substantially triggered apoptosis in the SCC15 cells. The findings were validated by triggering the apoptosis signalling mechanism, which resulted in dramatically increased pro-apoptotic and cleaved caspase-3 production while reducing anti-apoptotic protein Bcl-2 levels as contrasted to the control group. He found that fractions of MO leaves were capable of effectively suppressing the development of colonies and migration of cells in the SCC15 cells. Al-Asmari et al. documented that the administration of MOLE led to the interruption of the cell cycle at the stage of G2/M in tumour cells [30]. Tumour growth is characterized by the migration of cells and colony formation. The colony formation analysis was employed for examining the cell viability and growth of tumour cells determined by the propensity of individual cells to develop into cell clusters. The wound closure assays enable to make observations of cell movement in cultured cells [31]. Prior comprehensive investigations by Sreelatha et al. [7], and Sreelatha and Padma [14] demonstrated the cytotoxic impact of MOLE on KB cells along with their ability to trigger apoptosis and antiproliferative properties in KB cells. The MTT assay demonstrated that the hot water MOLE at 100 µg/mL exhibited a decrease in cell viability of around 38%. Furthermore, increasing its concentration to 200 µg/mL led to a decline in cell viability of 60%. Therefore, the MOLE effectively suppressed the KB cell growth to a degree that was contingent on the dosage.

Several morphological alterations indicative of cell death were detected in the treated cells, including shrinkage of the cytoplasmic membrane, loss of interaction with adjacent cells, the development of membrane blebs, and the occurrence of apoptotic bodies. Propidium iodide (PI), a fluorescent intercalating compound, binds to DNA and visualizes cell nuclei. In addition, PI is employed as an indicator of the degree of apoptosis in cells, as it is too large to penetrate the intact cell membrane of cells that are alive but is progressively capable of entering cells that are enduring apoptosis. Specifically, cells treated with a concentration of 200 µg/mL of MOLE exhibited nuclear shrinkage, DNA condensation, and disintegration. The study presents the potent anticancer effects of MOLE on KB cells and is accomplished by using elevating expressions of ROS within the cell and causing fragmentation of DNA [7] Additionally, several investigations have shown comparable findings [16, 32].

Berkovich et al. [33] demonstrated that the MOLE not only exhibits cytotoxic effects on Panc-1 cells but also has the potential to significantly enhance the efficacy of cisplatin when employed as a combination. The findings of Jung et al. indicate that the MOLE induces apoptosis in A549 cells by disrupting the process of gene translation [34]. The individual chemicals thiocarbamate and isothiocyanate found in MO can prevent the growth of malignant cells [35, 36] The fraction of dichloromethane has been identified to have cytotoxic effects on MCF7 cancer cells [37] Niazimincin serves as a potent chemopreventive substance in the process of carcinogenesis [38]. The extracts obtained from fruits and leaves, which include alcohol and methane, have demonstrated a noteworthy inhibition of tumour growth in animal models of melanoma [39]. Cold distilled water from Moringa, when soluble, hindered the growth of tumour cells and decreased the presence of ROS in cancerous cells [40] According to a recent computer modelling investigation, MO has been reported to contain rutin, which has the strongest binding capacity with BRAC-1, a gene associated with breast cancer [41].

The majority of the phytocomponents have demonstrated efficacy against many diseases, including cancer, which is believed to be attributed to the existence of bioactive molecules. Nano-particles developed as a result of targeted treatments, have proven to be highly efficient in a range of scientific fields owing to their minuscule dimensions. Green synthesis holds great promise for producing gold nanoparticles using indigenous vegetation and trees, like MO. The utilization of indigenous plants and trees, such as MO, in the manufacture of gold nanoparticles, has significant potential for green synthesis. The resulting gold phytonanoparticles have practical applications in cancer treatments, leading to enhanced chances of survival and improved quality of life [42] The binding energy, a crucial parameter between the protein and ligand is produced by the molecular docking process. This presents information regarding the affinity and potency of protein and ligand-receptor docking. As the binding energy decreases, the binding capacity and docking increase. The protein data that have previously been uploaded to various databases may not be identical to one another due to variations in the procedures used. Future perspectives for this arena of research involve comparing the protein structures that are acquired from various databases with various experimental models, instruments, and software. Additionally, it is imperative to evaluate the protein and gene regulation in both laboratory experiments and living organisms to confirm the computational predictions [4].

After much investigation, it has been determined that Moringa oleifera has many advantages for the human population. It is a good pharmacological choice for anti-cancer and anti-apoptotic applications because of its strong antioxidant content and diverse nutritional and phytoconstituent makeup.

Nevertheless, the present review was subjected to certain limitations. The different studies employed diverse extraction methods and solvents, potentially contributing to the disparities in findings caused by varying quantities of active chemicals in the extracted substance. Further research is required to determine any variations in the anticancer effectiveness resulting from the various extraction methods and solvents utilized. The current review included studies from in-vitro and animal models since sufficient human trials were not conducted. Future studies on human cells are required to prove the extensive potential of Moringa oleifera.

Conclusion

The studies chosen for review revealed that MO plant components have antioxidant, anti-inflammatory, anticancer, and chemopreventive properties. The results presented here indicate that MO extracts have tremendous potential as drugs against cancer. Additionally, using Moringa alongside chemoprevention could help improve the overall immune response and reduce chemotherapy-induced toxicity, such as oxidative damage to healthy cells. Although more clinical trials are needed to fully establish its efficacy and safety as a complementary therapy, the growing body of evidence positions Moringa oleifera as a promising natural adjunct to cancer treatment strategies.

Author contributions

C R: Conceptualization; investigation; writing—original draft; writing—review and editing. S R: Conceptualization; writing—original draft; writing—review and editing. V P V: Investigation; review and editing. A P F: Conceptualization; writing—review and editing. P M: Project administration; review and editing. U M: Conceptualization; review and editing.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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