A Scoping Review on Cucumis melo and Its Anti-Cancer Properties

Cucumis melo L., better known by its popular cultivar cantaloupe, is an economically significant crop in the Cucurbitaceae family. Melon peel and seeds have shown medicinal potential due to their numerous biological qualities, including anti-inflammatory, anti-cancer, antibacterial, hepatoprotective and immunomodulatory effects to treat cardiovascular disease, diabetes and oedema. This scoping review aims to broaden the research scope on the cancer-fighting abilities of melon extract and its half maximal inhibitory concentration (IC50). Three databases which are Scopus, ScienceDirect and PubMed were used to locate relevant publications utilising the keywords ‘melon’, ‘Cucumis melo’, ‘inhibitory activity’, ‘cancer’ and ‘anti-cancer’. The Preferred Reporting Items for Systematic and Meta-analyses extension for Scoping Review (PRISMA-ScR) framework was used in conducting this study. Out of 904 articles, 14 articles met the inclusion criteria and were used in this analysis. These articles were published in English between 2000 and 2023 with full text accessibility, specifically addressed the fruit cantaloupe (Cucumis melo L.) or melon and reported on any type of cancer. Cucumis melo extract showed promising anti-cancer action in both in vitro and in vivo investigations on eight different cancer types: cervical, colon, prostate, leukaemia, multiple myeloma, breast, hepatoma and ovarian cancer. A thorough analysis shows that some of the IC50 values were significantly low, especially in cases of colon and prostate cancer, indicating a significant anti-cancer effect. The substantial anti-cancer benefits of Cucumis melo fruit extracts point to the necessity for additional investigation into their potential for cancer therapy on each form of cancer.


Introduction
Cucumis melo L., commonly referred to as the well-known melon cultivar cantaloupe, is a commercially important crop belonging to the Cucurbitaceae family (1)(2)(3).The fruit parts are eaten, while the peels and seeds are discarded.According Rolim et al. (4), increasing fruit consumption increases the volume of waste generated, notably the peels and seeds.These melon peels and seeds have shown medicinal potential (4)(5)(6).For example, the oil extracted from seed contains a high concentration of aiding in the preservation of nutrients (8).It has been discovered that all components of the melon, even the seeds and peels, have their own health benefits.
Melon varieties have shown several biological properties towards human health.For many years, numerous traditional medicine systems have employed various melon species including Cucumis melo L. to cure a variety of illnesses, such as cardiovascular disease, diabetes and oedema.The melon also possesses anti-inflammation, anti-cancer, antibacterial, hepatoprotective and immunomodulatory properties (9,10).Despite this, few studies have highlighted the anti-cancer properties of Cucumis melo for each form of cancer.The cytotoxicity of muskmelon fruit and seed extract has been studied (4,11) though these studies were only conducted on one cancer cell type and extract from one plant part either seeds, peel or whole fruit (12).Therefore, a thorough scoping study of Cucumis melo and its anticancer properties was performed by reviewing and compiling the current literature on the anticancer effects of melon extracts and the halfmaximal inhibitory concentration (IC 50 ) values of these extracts.

Methods
The purpose of this study was to provide a broad review of the most recent research on Cucumis melo extract and its anti-cancer properties.This scoping review was carried out in compliance with the Preferred Reporting Items for Systematic and Meta-analyses extension for Scoping Review (PRISMA-ScR) by Tricco et al. (13) which comprise identification, screening and eligibility, and included articles in the flow diagram (Figure 1).

Identifying the Research Question
The review questions are: i) What are the anti-cancer properties of the melon?ii) What are the half-maximal inhibitory concentrations (IC 50 ) values of melon extracts in the treatment of cancer cells?

Distinguishing Relevant Studies
English academic journal articles published between 2000 and 2023 were searched using electronic database searches with PubMed, Scopus and ScienceDirect.The search included all study types but did not include systematic reviews or review articles.The researchers separately assessed the eligibility of titles, abstracts and keywords.Out of 904 articles found using electronic databases, 14 studies were included in this review.Figure 1 shows the flow diagram of data selection.The keywords used were 'melon' AND 'inhibitory activity', 'melon' AND 'anti-cancer', 'melon' AND 'inhibitory activity' AND 'cancer', and 'Cucumis melo' AND ('anti-cancer' OR 'MTT assay' OR 'cell viability') with Boolean terms AND/OR to combine or separate the keywords as shown in Table 1 and Table 2.

Selecting Studies
The identified studies must satisfy the following eligibility criteria to be included in this review: i) fruits involved were of cantaloupe, Cucumis melo L. or melon; ii) reported on any type of cancer and iii) has full text accessibility.

Charting the Data
The data were summarised in a table form which includes the author, year of publication, country, fruit parts, pure compound/crude extract, human cancer line/tumour xenograft, IC 50 , concentration used and main findings.

Collating, Summarising and Reporting the Results
The collected results were subsequently compiled and summarised.Based on the study's limitations that were discovered in the chosen articles, the research gaps were emphasised.

Results
Three databases yielded a total of 904 publications: 739 publications in ScienceDirect, 126 publications in Scopus and 39 publications in PubMed (Figure 1).The articles were uploaded to Mendeley and checked for duplication.A total of 226 articles were removed and the remaining 678 articles were evaluated for eligibility based on the title and abstract.A total of 634 articles were excluded due to ineligibility determined by their titles and an additional 30 articles were excluded based on the ineligibility criteria outlined in their abstracts.Those articles were disregarded since they did not underline the anti-cancer properties or focus on Cucumis melo.Only 14 articles were included and further analysed because they matched the predetermined inclusion requirements.lung fibroblast cells (HLF), human glioblastoma multiforme cells (GBM8401), colorectal carcinoma cells (RCM-1), lymphoblast cells (K562), cervical carcinoma cells (SiHa), kidney carcinoma cells (786-0), mouse lymphoma cells (L5178Y) and rat brain cells (PC12) (n = 1, 7.1%) (Table 4).Meanwhile, the in vivo assessments incorporated tumour xenograft in mice.

Characteristics of Study
From the year 2000 to 2010, only two studies (n = 2, 14.2%) were conducted regarding Cucumis melo and its anti-cancer properties.Since then, from 2011 to 2023, there have been a considerable rise in research (n = 12, 85.7%) evaluating the effectiveness of Cucumis melo extract as an anti-cancer agent (Table 3).China has the most discoveries in this field of study (n = 7, 50.0%) followed by Egypt (n = 2, 14.2%), Brazil, Iran, India, Japan and Taiwan (n = 1, 7.1%).All studies conducted in vitro evaluation (n = 14, 100%) including both human and animal cell lines and four of these also incorporated in vivo studies (n = 4, 28.6%) A variety of human cancer cell lines were employed in an extensive number of in vitro research evaluations.The most used cancer cell lines were cervical cancer cells (HeLa), adenocarcinomic human alveolar basal epithelial cells (A549), (n = 3, 21.4%), followed by breast cancer cells (MCF-7), colorectal adenocarcinoma cells (HT-29), colon adenocarcinoma cells (HCT-116), prostate cancer cells (PC-3) (n = 2, 14.2%) and hepatoma cancer cells (BEL-7402), human non-small cell lung carcinoma (H1299), human
In comparison to other cancer types, the anti-cancer activities of Cucumis melo extract against HCT-116 (12, 14) and HT-29 (4,24) cell lines are the subject of the greatest research on melon anti-cancer properties (Table 7).In contrast to the study by Ibrahim et al. (14), which found an IC 50 of 92.624 mg/mL for HCT-116, Zhang et al. (12) found the most potent IC 50 at 0.25 mg/mL for seed chloroform extract and 0.26 mg/mL for whole fruit methanol extract (Table 8).Strong cytotoxic effects of Cucumis melo fruit extracts have also been reported by Ittiyavirah et al. (11) and Zhang et al. (12) against the PC-3 cell line.Ittiyavirah et al. (11) reported an IC 50 of 1.47 mg/mL, whereas Zhang et al. (12) achieved an even more remarkable IC 50 of about 0.34 mg/mL.These results demonstrate the noteworthy influence of Cucumis melo fruit extracts on prostate cancer and point to a promising direction for future studies in cancer therapy.(12).The entire Cucurbitaceae family has several health benefits, with each fruit or vegetable having a distinct impact on human health (25).Cucumis melo is widely recognised for its advantageous pharmacological properties, which include anti-inflammatory, antioxidant, hepatoprotective, diuretic, anti-cancer, anti-ulcer and immunomodulatory effects (26).Notably, Cucumis melo contains bioactive substances that have shown anti-cancer effects, including cucumol A, cucumol B, phenolic compounds, protein trypsin inhibitor, MTA, CuB and CuE.
CuB is the most common and active compound among the cucurbitacin class and has attracted much interest from researchers worldwide (27).According to Zhang et al. (28) 21) and shows potential as a therapy agent for non-small cell lung cancer (30,31).Further investigation by Yuan et al. (19) showed that CuB induced TLR4/NLRP3/GSDMDdependent pyroptosis to suppress non-small cell lung cancer by elevating reactive oxygen species (ROS) and Ca 2+ , which may represent a viable target for treatment for this cancer type.
Additionally, Bajcsik et al. (32) identified CuE as a notable phytomolecule that is frequently present in therapeutic food plants from the Cucurbitaceae family.CuE is well known for its strong therapeutic potential.It has anti-inflammatory, immunomodulatory, hepatoprotective, and anti-cancer properties.For instance, an in vitro study by Hsu et al. (33) revealed that CuE therapy prevented brain metastasis of non-small cell lung cancer in mice model experiments, as well as the expression of yes-associated protein (YAP) and its downstream signalling genes in non-small cell lung cancer.CuE also had an anti-proliferative effect on A549 cells by acting as a tyrosine kinase inhibitor and interfering with the EGFR/MAPK signalling pathway (21).This comprehensive scoping study evaluated the cytotoxic effects of Cucumis melo extract and its IC 50 on several different cancer types.Cucumis melo might be capable of inhibiting nine different cancer types.The IC 50 values of the extracts on the different cancer types ranged widely from 0.247 mg/mL to 178.384 mg/mL.Notably, the extract showed an outstanding IC 50 of 0.24693 mg/mL on HCT 116 cell lines, indicating its potent inhibitory effect.The extract had the most inhibitory potency on HCT 116 when compared to the other cell lines (PC-3, Jurkat and HeLa) in the same investigation carried out by Zhang et al. (12).Furthermore, Li et al. (24) highlighted the correlation between stronger anti-proliferative efficiency and lower IC 50 values.
Remarkably, the chloroform seed extract showed the greatest cytotoxicity, indicating an enhanced concentration of seed-derived bioactive substances.This association between higher levels of bioactive chemicals and enhanced cytotoxicity is consistent with previous research highlighting the direct connection between the quantity of active metabolites in plant extracts and their biological activities (34)(35)(36).Cucumol A, which is isolated from the seeds, showed significant cytotoxic action against HeLa cells and murine lymphoma cells (L5178Y) in a study conducted by Ibrahim et al. (14).Additionally, cucumol B, a new triterpene benzoate from Cucumis melo seeds, also acted as a cytotoxic agent on SKOV-3, MCF-7 and HCT 116 cells, as demonstrated by Ibrahim et al. (15).Terpenoids, especially those from cucurbitaceous plants, have been shown to exhibit chemopreventive and chemotherapeutic effects against various cancer types (15,37).
Previously established research has demonstrated the efficacy of protease inhibitors in mitigating the risk of cancer development by inhibiting angiogenesis (38).A recent in vivo evaluation by Rezaei et al. (20) further substantiates this understanding, particularly focusing on a trypsin inhibitor extracted from Cucumis melo seeds.They showed that the trypsin inhibitor induced necrosis in tumour tissue, simultaneously suppressing the expression of pivotal genes associated with angiogenesis, such as matrix metalloproteinase genes (MMP-2, MMP-9) and vascular endothelial growth factor (VEGF).Moreover, the inhibitor manifested a dose-dependent positive influence on various tumour parameters, including height, width, depth and other crucial tissue characteristics.
This extensive body of research highlights the potential of Cucumis melo seed extracts as a source of various bioactive compounds with remarkable cytotoxic effects on a variety of cancer cell lines.These findings highlight the potential therapeutic use of trypsin inhibitors extracted from Cucumis melo seeds in treating cancer and provide insight into the complex ways in which these agents affect angiogenesis inhibition and other important aspects of tumour progression.The potentials of Cucumis melo extract as a powerful source of anti-cancer drugs are strengthened by this review.The data presented in this scoping review underscore the necessity of further investigation into the potential therapeutic uses of Cucumis melo in cancer treatment.
Even though most of the studies showed a positive effect of Cucumis melo on cancer treatment, this scoping review found a few research gaps.Firstly, the anti-cancer properties of melon extract have not been studied with respect to all types of cancer.This limitation in the scope of research raises the possibility that the observed treatment efficacy may be much more significant in malignancies that have not yet been investigated.Secondly, the publications did not emphasise the phytochemicals' or the bioactive compound's synergistic effects on prevention and treatment inside the crude extract.Thirdly, the evaluation of melon extract's efficacy in treating cancer in vivo was limited to tumour xenografts.Prior to clinical trials, more information on in vivo study on dosages, administration modalities and immune systemcancer cell interactions is required.Finally, no clinical trial evaluations were provided despite the potent anti-cancer characteristics of melon extract in vitro and in vivo, highlighting the necessity for further investigation into the efficacy, efficiency, long-term impacts and safety prior to approving melon extract as a cancer treatment agent.

Conclusion
This scoping study highlights the remarkable anti-cancer activities of Cucumis melo extract against a range of malignancies, including leukaemia, multiple myeloma, breast, hepatoma, ovarian, colon, prostate and cervical cancer.The measured IC 50 values, which ranged from 0.247 mg/mL to 178.384 mg/mL, show the difference in the potency of Cucumis melo extracts against different cancer cells.Additionally, some bioactive compounds found in Cucumis melo, including cucumol A, cucumol B, CuB, CuE, protein trypsin inhibitor and MTA, significantly suppress the growth of certain cancer kinds.Notably, the evaluation primarily employed human cancer cell lines for in vitro studies, while murine models were utilised for in vivo investigations.
The scoping review reveals several remarkable IC 50 values of Cucumis melo extract, particularly against colon and prostate cancer cells, suggesting a prominent anti-cancer effect.A comparison of the IC 50 values from two distinct investigations revealed a pattern, with the most recent studies providing a more potent IC 50 inhibitor value in contrast to the earlier research.For a thorough understanding, further combination studies are necessary to determine whether the in vitro synergy is also present in animal models.It is crucial to investigate drug interactions, especially in cases of prostate and colon cancers as it shows potential for future cancer therapy.Further research aimed at bridging the gap between in vitro and in vivo settings and exploring pathways in various cancer types will help us better grasp the therapeutic potential of Cucumis melo and explore the safety issues.

Table 1 .
Keywords and search strings used in electronic database search

Table 2 .
The process of selecting keywords in electronic databases through the utilisation of Boolean search operators

Table 6 .
14)i-cancer properties of Cucumis melo and its half maximal inhibitory concentration (IC 50 ) of reviewed studies (n =14)

Table 7 .
Studies of anti-cancer effects of melon on several types of cancer Notes: CuB = Cucurbitacin B; CuE = Cucurbitacin E; MTA = methylthio acetic acid

Table 8 .
Anti-cancer effects of melon on several type of cancer with its half maximal inhibitory concentration (IC 50 )