Cancer is an uncontrolled division of abnormal cells that can potentially intrude or spread (metastasize) to other body regions (Singla et al., 2022c; Chavda et al., 2023). Cancer is a collection of more than 100 different disorders rather than a single disease. It is an uncontrolled cell division that causes abnormal cell development and spread. These malignant cells may infiltrate other tissues and spread to other body parts (metastasize). Cancer is a collection of over 100 different ailments instead of a single disease. Cancer is the world’s second leading cause of death, accounting for 7.6 million deaths in 2005 (Abbas and Rehman, 2018). Globally, an estimated 11 million people have been diagnosed with cancer, which was expected to climb to 16 million by 2020 (Sarfati et al., 2016). According to estimates, one-third of all new cancer cases may be cured if properly diagnosed and treated (Wang et al., 2013; Ricks, 2015). Chemotherapy is a cancer treatment that is widely used. Because cancer cells lack many of the regulatory processes normal cells have, they continue to divide even when normal cells do not. Chemotherapeutic medicines are more sensitive to cancer cells with this characteristic (Zugazagoitia et al., 2016; Prager et al., 2018). A substantial collection of useful chemotherapeutic drugs has been established after almost five decades of systemic medication research and development. Chemotherapeutics, on the other hand, are not without their own set of issues. Chemotherapeutic treatments can result in a wide range of side effects. 5-fluorouracil, for example, is known to produce myelotoxicity (Klein et al., 2022) and cardiotoxicity (Labianca et al., 1982), and has even been demonstrated to serve as a vasospastic agent, in rare but recorded occurrences (Rastogi et al., 1993). Doxorubicin, another commonly used chemotherapeutic, has been linked to cardiac toxicity (Avilés et al., 1993; Desai et al., 2008; Damiani et al., 2016), renal toxicity (Varela-López et al., 2019), and myelotoxicity (Pourtier-Manzanedo et al., 1995). The toxicity of chemotherapeutic drugs can be a severe problem when treating cancer using allopathy or traditional medicine (Zugazagoitia et al., 2016; Gezici and Şekeroğlu, 2019). Like chemotherapy, natural products also play an essential role in preventing cancer (Rani et al., 2022). Plants consist of various phytochemicals which are responsible for anticancer activity. The structure of natural plant chemicals varies greatly; many are aromatic compounds, most of which are phenols or their oxygen-substituted counterparts. It is beneficial to focus on active phytochemicals for herbal therapy to minimize the adverse effects, as well as pathogenic resistance against antibiotics (Kooti et al., 2017). Plants produce a large number of secondary metabolites that are biosynthetically derived from primary metabolites and are a major source of microbicides, insecticides, and a variety of pharmaceutical medications (Garg et al., 2022; Babbar et al., 2023; Kumar et al., 2023). Medicinal plants or their secondary metabolites have played an essential role in human society for a long time in combating diseases, either directly or indirectly (Greenwell and Rahman, 2015; Sharma et al., 2022). Despite the availability of various synthetic antitumor drugs, researchers are still looking for potent naturally occurring anticarcinogens that can prevent, delay, or reverse cancer progression (Singla et al., 2022b). Plants are essential in cancer treatment (Singla et al., 2021a; Singla et al., 2022a). Plant-derived chemicals are thought to account for more than half of all anticancer drugs (Omara et al., 2020). Plant extracts were employed to cure a variety of ailments, and this is the foundation of all Indian medical systems (Singla et al., 2021b). However, compared to modern medicine, this subject is underdeveloped owing to a lack of scientific documentation in this field (Chanchal et al., 2017).

Natural foods and food-derived antioxidants, such as vitamins and phenolic phytochemicals, have recently gotten much attention because they protect against oxidative damage and genotoxicity. During the last 20 years, demand for fresh and ready-to-eat items has increased interest in minimally processed fruits and vegetables, which combine freshness and convenience (Kim et al., 1993). Plant forms have long been known to provide medical benefits (Pandey et al., 2023). This review comprehensively summarizes the anticancer attributes of the phytochemicals found in Opuntia ficus-indica (L.) Mill. Several species of cactus pear plants (Cactaceae family) evolved in Central America (Mexico). In folk medicine, Opuntia fruits and young stems have long been used to treat diseases such as hypertension, diabetes, allergies and asthma, burns, swelling, and nausea. (Abou-Elella and Ali, 2014). The most significant bioactive substances found in cactus fruit are betaxanthin, betacyanin, and phenolic compounds, which all have potent antioxidant capabilities (Gentile, 2004; Kuti, 2004). Phenolic compounds, especially their effective variants, have an aromatic ring bearing one or more hydroxyl groups. Both chemical compositions and concentrations vary considerably depending on the kind of plant tissue, variety, and ripening phases. Cactaceae plants and fruits have been shown to contain glycosylated flavonols, dihydroflavonols, flavonones, and flavonols (Kuti, 2000). Cactus pear fruit is a crucial product for protecting human health against degenerative diseases like cancer, diabetes, hyperglycemia, hypercholesterolemia, arteriosclerosis, and gastric ailments because of the phenolic compounds’ antioxidant qualities (Galati et al., 2003). O. ficus-indica’s polyphenolic chemicals have been demonstrated to cause the plasma membrane to become hyperpolarized and to increase the intracellular calcium pool in human Jurkat T-cell strains (Aires et al., 2004).

An extensive survey of the chemical composition and pharmacological activities of Opuntia ficus-indica (L.) Mill. was conducted in scientific databases, including Research Gate, Pubmed, Scopus, Science Direct, Web of Science, and Google Scholar. The search terms “Opuntia ficus-indica,” “Opuntia ficus-indica and biological activity,” “Opuntia ficus-indica and pharmacological activity,” “Opuntia ficus-indica and chemical compounds,” and “Opuntia ficus-indica and chemical profile,” were used for data collection. One hundred and ten publications were included, from 1992 to 2022, from the articles focused on phytochemicals obtained from O. ficus-indica.

O. ficus-indica (L.) Mill., sometimes known as the prickly pear or nopal cactus, pertains to the Cactaceae family of dicotyledonous angiosperms, which comprises around 1500 species of cactus ( Figure 1A ). The plant O. ficus-indica is native to the tropics and subtropics (Abou-Elella and Ali, 2014). It can grow in arid and semi-arid environments and can be found in South Africa, Mexico, Latin America, and the Mediterranean region (El-Mostafa et al., 2014). Moroccan inhabitants now recognize three kinds of O. ficus-indica. The first is known as “Christians’ nopal” and is widely employed as a field barrier. It is made up of thorny cladodes. The second, cladodes of inermis, is known as “Muslims’ nopal” and is used as green feed for cattle. The final variation, “Moses’ nopal,” has huge inermis cladodes and produces a gigantic pear. It grows primarily in the south of Morocco (Madrigal-Santillán et al., 2022). The juice, jam, oil, and tea derived from the prickly pear of the nopal cactus are used in health, nutrition, and cosmetics (El-Mostafa et al., 2014). Indigenous peoples eat large amounts of fresh or dried fruits. Cactus cladodes, fruits, and flowers are highlighted in these populations due to their high antioxidant, pectin polysaccharide, and fiber content (Farag et al., 2020).

In several nations, it is utilized as an natural treatment for various health conditions (Slimen et al., 2017). Fresh or dried fruits are consumed in large quantities by indigenous people. Cactus cladodes, fruits, and flowers are promoted in these populations due to their pectin polysaccharide, high antioxidant, and fiber content (Lu et al., 2019). Recent scientific studies have emphasized the synthesis of many bioactive molecules that promote O. ficus-indica (L.) Mill medicinal uses and pharmacological characteristics. These molecules include carbohydrates, minerals, amino acids, fatty acids, vitamins, fibers, and secondary metabolites recognized for their antioxidant and anticancer properties (Trachtenberg and Mayer, 1981). The primary aim of this article is to summarize and emphasize the benefits of O. ficus-indica in terms of cancer prevention and treatment (Park and Chun, 2001).

We have searched PubMed using the search term “Opuntia ficus-indica,” and 628 articles were retrieved as of 02.06.2023 ( Figure 1B ), which covered 19 clinical trials articles, three metanalysis articles, 15 randomized controlled trial-based articles, 31 review articles, and four systematic reviews. Some of the countries that researched more on the topics oriented towards Opuntia ficus-indica are Italy (98), Brazil (38), Korea (37), Spain (37), France (35), Germany (26), South Africa (17), India (13), China (7), United States (5), Australia (5), and United Kingdom (5). When we processed the title and abstracts of those 628 articles in the VOSviewer, it yielded 16411 keywords. Once we set criteria for a minimum occurrence of a term five times, it resulted in 1229 terms. For each of the 1229 terms, a relevance score will be calculated and based on the score, and with a cutoff of 60% most relevant terms, it finally yielded 737 terms out of 628 articles. The top 10 keywords are given in Table 1 , and the overall interactions of all the keywords are illustrated in Figure 1C . The bigger the bubble is, the more it is dominant as keywords in the searched literature.

Nevertheless, we have observed only 1375 MeSH terms and 189 terms that have minimally appeared five times in the selected literature. The top 10 MeSH terms are given in Table 2 , and the overall MeSH term map is illustrated in Figure 2 . We could see the prevalence of work on Opuntia ficus-indica related to apoptosis, cell line tumor, antioxidants, cytoprotection, and reactive oxygen species. It reveals the strong potential of Opuntia ficus-indica as a therapeutic reservoir and further encourages us to explore the anticancer potential of Opuntia ficus-indica.

When the MeSH terms “Opuntia ficus-indica” and “Cancer” were searched on PubMed (dated 01.08.2023), it resulted in 23 articles, including one review article. When the publication data was processed in VOSviewer, it yielded 157 MeSH terms in the title and abstract of these articles. 48 MeSH terms have been repeated in a minimum of 2 publications. Figure 3 is the interactive mapping between these 48 MeSH terms. The most co-occurred MeSH terms were “opuntia,” “humans,” “antineoplastic agents, phytogenic,” “plant extracts,” “animals,” “apoptosis,” “phytotherapy,” “cell line, tumor,” “cell proliferation,” and “mice.” We could also observe other vital terms like skin neoplasms, melanoma, colonic neoplasms, HeLa cells, and many others.

While exploring Scopus for the articles published with the terms “Opuntia ficus-indica” and “cancer,” present in Title/Abstract/Keywords, yielded 62 documents. The analyze tool embedded within Scopus was further utilized to do the bibliometric analysis ( Figure 4 ). It has been observed that in the past five years, publications related to “Opuntia ficus-indica” and “cancer” have increased significantly ( Figure 4A ). Four research groups “Antunes-Ricardo, M. et al.,” “Attanzio, A. et al.,” “Livrea, M.A. et al.,” and “Tesoriere, L. et al.,” have published four papers each ( Figure 4B ). Top-most cited article from Antunes-Ricardo, M. et al. was “Induction of Apoptosis in Colon Cancer Cells Treated with Isorhamnetin Glycosides from Opuntia ficus-indica Pads” with 71 citations as of date (Antunes-Ricardo et al., 2014). The top-most cited article from Attanzio, A. et al., Livrea, M.A. et al., and Tesoriere, L. et al. was the same. It was entitled “Antiproliferative and pro-apoptotic activity of whole extract and isolated indicaxanthin from Opuntia ficus-indica associated with re-activation of the onco-suppressor p16INK4a gene in human colorectal carcinoma (Caco-2) cells” with 50 citations as on date (Naselli et al., 2014). Of 62 documents, 69.4% were articles, followed by 22.6% review articles ( Figure 4C ), and Italy was recorded as the country with the highest number of documents, followed by Mexico and South Korea ( Figure 4D ).

When the bibliometric data from these 62 Scopus-retrieved documents were extracted and imported in VOSviewer, there were 1891 indexed keywords. Of these 1891 indexed terms, 59 are visible in at least five publications. Before analysis, some indexed keywords were manually removed like “human,” “humans,” “nonhuman,” “chemistry,” “article,” “plant extracts,” “animal,” “animals,” “priority journal,” “review,” “isolation and purification,” “human cell,” “animal experiment,” “animal tissue,” “mice,” “drug mechanism,” and “procedures.” Figure 5 illustrates the interactive mapping between the selected indexed keywords retrieved from these 62 documents. Along with the Opuntia ficus-indica and cancer-specific terms, important co-occurring terms were oxidative stress, antioxidants, anti-inflammatory activity, and diabetes mellitus. Indicaxanthin was strongly connected with cell proliferation and antineoplastic agents. Cell proliferation seems to strongly associate with oxidative stress and lipid peroxidation as a co-occurred term.

In several studies, abundant Opuntia parts, including prickly pear fruits, seeds, peels, stems, cladodes, and roots, have been shown to have cytotoxic effects on malignant cell lines ( Table 3 ). Antunes-Ricardo et al. (Antunes-Ricardo et al., 2014) investigated the cytotoxic activity of purified isorhamnetin glycosides or cladode flour extracts of O. ficus-indica (var. Jalpa) on two types of cancer cell lines of the human colon, Caco-2, and HT-29, which represent apoptosis-resistant and apoptosis-susceptible cell lines, successively, with normal fibroblasts (NIH 3T3) were employed as control. According to these authors, the glycosylation pattern of pure isorhamnetin glycosides and extract of cladode flour was more cytotoxic to HT-29 cells than Caco-2 cells. The induction of apoptosis by the caspase cascade, which plays a crucial role in apoptosis pathways, was linked to these effects. Naselli et al. (Naselli et al., 2014) analyzed the results of an aqueous fruit extract of O. ficus-indica on the growth of the Caco-2 cancer cell line of the human colon. On proliferating cells, these researchers found no effect on the differentiated cells but a dose-dependent apoptotic effect. This research shows an epigenomic effect on the tumor suppressor gene p16INK4a due to the demethylation of its promoter and stimulation of its expression, indicaxanthin. Betanin, obtained from fruits of O. ficus-indica, was found to suppress the development of the human’s chronic myeloid leukemia cell line K562 via the apoptotic intrinsic pathway (Sreekanth et al., 2007).

The toxicity impact from prickly pear fruits-filtered juices of several species of Opuntia on various cancer cell lines was investigated by Chavez-Santoscoy et al. (Chavez-Santoscoy et al., 2009). The Caco-2 and PC3 prostate cell lines were most impacted, whereas hepatic HepG2 and mammary gland MCF-7 cell lines grew slower. As a control, normal fibroblasts were used. On cancer cells, O. rastrera was the most cytotoxic species, with the highest potential and antioxidant content amongst the distinct species exposed to be tested. Kim et al. demonstrated that cladodes extracts from O. humifusa may cause apoptosis in human colon SW-480 and MCF-7 cells (Kim et al., 2015). Water-separated fractions of O. humifusa stems and fruits suppressed the development of U87MG glioblastoma cells, which was related to cell proliferation and reactive oxygen species (ROS) production (Hahm et al., 2010). The same researchers reported a similar effect on HeLa cancer cells but not on usual fibroblasts (Hahm et al., 2014). Serra et al. (Serra et al., 2013) reported that juice concentrates rich with polyphenols from several Opuntia were found to be cytotoxic to colorectal cancer cell lines HT- 29 but hardly toxic to Caco-2 and that cell-cycle arrest in the same cells was induced more efficiently by the natural juice remnants extracts (peels and seeds) than juice concentrates. Surprisingly, this effect was associated with a rise in ROS in the cells, suggesting that extracts’ pro-oxidant effects caused cell death induced by ROS. Feugang et al. (Feugang et al., 2010) observed a similar pro-oxidant effect in ovarian cancer cells when compared to immortalized or normal cells. It is essential to use relevant controls, such as cells of the same type with the same genotype, to make conclusions about compounds’ potential benefits. (Phyto)-compounds could be more cytotoxic to cancer cells than their non-cancerous counterparts to be considered as anti-cancer compounds (Keller et al., 2015). Furthermore, various Opuntia cladode flours protect against the cytotoxicity of 4-hydroxynonenal, an oxidation product of dietary lipids that may have a role in promoting red meat for colorectal cancer. Only the usual epithelial cells of the mouse colon showed the protective effect, not on the similar cells that had the Apc type of mutation, whichever is an early phenomenon of colorectal oncogenesis prevalent in humans (Karim and Huso, 2013). Nevertheless, validating the effects seen in vitro and in vivo studies is essential. Zou et al. observed that aqueous extracts of Opuntia cactus pear inhibited carcinogenesis in nude mice to a similar extent as the synthetic retinamide (4-HPR) retinoid N-(4-hydroxyphenyl) employed as a chemotherapeutic dummy compound (Zou et al., 2005). Hahm et al. demonstrated that O. humifusa had a protective effect on HeLa cell xenografts (Hahm et al., 2010). Some researchers noted that cladode extracts of O. ficus-indica reduced genotoxicity and oxidative stress caused by the aflatoxin B1 and mycotoxins zearalenone in vivo (Zourgui et al., 2008). Extracts of Opuntia were usually administered into the peritoneal cavity. To determine the protective effects of Opuntia spp. additional studies are required, including evaluating the compounds by an oral route or in a more physiological condition that takes into consideration the digestion and bioavailability of compounds alike. In such an approach, in two distinct animal models of skin carcinogenesis, lyophilized powder of O. humifusa fruit administered through pelletized food was found to be protecting with a decline in inflammation and skin lipid peroxidation (Lee et al., 2012; Lee et al., 2013). All these findings suggest that Opuntia spp., whether in the form of fruits, nopal (Opuntia cladodes or stems), or fruit juice, might be an effective anticancer approach.

Opuntia ficus-indica is known to have various phytochemicals, which are discussed below.

O. ficus-indica contains various phytochemicals ranging from phenolic acids to phytosterols ( Figure 11 ). Many phytochemicals like quercetin, hesperidin, and linolenic acid have already been evaluated and proven to have multifarious therapeutic potentials. However, it seems like more in-depth studies are required to validate the translational potential of O. ficus-indica to reach bedside.

Searching on PubMed for O. ficus-indica and cancer-related papers yielded 18 results on 02.06.2023 while searching for O. ficus-indica and apoptosis-related papers resulted in 9 papers as of 03.06.2023. These studies indicate the increasing interest of researchers to examining anticancer potential of this plant. However, it is still quite low quantitatively and more in-depth research is utmost needed in this direction. Upon removal of duplicates, 21 articles were processed for quantitative data analysis (QDA). Some of the most prominent terminologies found to be “Opuntia ficus-indica,” “extract,” “indicaxanthin,” “kaempferol,” “glycoside,” “Opuntia,” “cancer,” “colorectal/colon cancer,” and “apoptosis.” ( Figure 12 ) Indicaxanthin, kaempferol, and isorhamnetin glycosides were most studied as anticancer agents in those studies ( Figure 13A ). When we looked for the prevalence of the phytochemical class mentioned repeatedly in those 21 articles, we had observed that glycosides dominate, followed by flavonoids and betalains ( Figure 13B ). Most anticancer studies on O. ficus-indica and its purified metabolites are related to colorectal/colon cancer, followed by melanoma and breast cancer ( Figure 14 ). Very little attention has been paid to leukemia, thyroid, endometrial, liver, and prostate cancer, and it should be considered an opportunity for the researchers to explore O. ficus-indica and its metabolites for these heterogenous cancers. The most notable mechanisms expressed and validated in those studies were apoptosis, cell cycle arrest (G0/G1 and G2/M), Bcl-2 modulation, antiproliferative, oxidative stress-mediated mechanisms, and cytochrome c ( Figure 15 ). We have also observed that cladodes and fruits of O. ficus-indica have been more studied than other plant parts, which again opens opportunities for researchers to explore. Further, cell line-based studies dominated, and there were very few studies related to animal-based experiments. The Zebrafish model has also been utilized by one group, and it could open a new platform for others to explore.

In this article, we discussed the effectiveness of O. ficus-indica against most death-causing diseases, including cancer. Traditional chemo- and radiotherapies can weaken the patient due to their toxic and destructive effects on normal cells. The O. ficus-indica plant is a natural means that can be used for the prevention and cure of cancer without any serious side-effects. Various phytochemicals are present in O. ficus-indica, which includes flavonoids, polyphenols, betalains, and tannins, which possess various biological activities such as antimicrobial, anti-inflammatory, antioxidant, and most essential, anticancer activity. Based on the available literature we provided in this study, investigations using diverse cancer cell lines have shown compelling evidence of anticancer activity. Only a few investigations employing in vivo tumor models have produced comparable results. Currently, very little information is available on whether concentrations demonstrating activity in vitro are attainable in the blood or serum of laboratory animals. While this is a restriction in our current knowledge of the anticancer potential of plants in the Cactaceae family, future studies are likely to examine this to next level. We believe that the significance of our review lies in drawing the scientific community’s attention to this plant family, which is, on the one hand, auspicious in terms of cancer treatment and prevention, but on the other hand, remains mostly unexplored.

JW, NR, SJ, RR, SK, SaK, SvK, BD, JS-G, BS, and RKS wrote different manuscript sections. NR, RKS, and BS laid down the idea and manuscript outline and compiled and finalized the manuscript. BS arranged the funding source. All the authors have reviewed the final version of the manuscript.