Several types of plants species can efficiently grow and reproduce in high-salinity, dry environments and under drought conditions. These plants have the ability to resist high salinity by modifying their biological and natural properties, including morphologies ^[1][2][3][40,41,42]. Such plants are scientifically categorized as halophytes, and include more than 1500 species found on all continents of the globe, except Antarctica ^[4][43]. The halophytic flora are therefore widely distributed in marshy areas, coastal locations, sandy beaches, and large swaths of deserts with low rainfall, including the mountains across the Arabian desert, plains, and prairies, where the salinity of the soil is comparatively very high in relation to normal tropical and sub-tropical soils ^[5][6][7][8][44,45,46,47]. Figure 1 shows some of the halophytic plants growing in the deep desert areas of the central region of the Kingdom of Saudi Arabia.

Halophytes, which have the ability to overcome the abiotic oxidative stress of high salinity on a more elaborate scale, can do so because of the presence of several antioxidant enzymes and related secondary metabolites produced through the activity of the plants’ inherent enzyme systems, together with the adaptive nature of the plant species; this adaptation is gained through exposure to environmental hardships ^{[9][10][11][12]}[48,49,50,51]. The enzymatic defense system includes superoxide dismutase, catalases, ascorbate peroxidases, and glutathione reductase ^[13][52]. The enzymatic system plays an elaborate part in various defense mechanisms of these plants which participate through various physiological functions and the biochemical pathways responsible for them. The antioxidant secondary metabolites produced in the halophytes, as a product of the enzymatic activities, act as part of a non-enzymatic defense system ^[14][15][53,54]. This system includes the presence of phenolic compounds of phenylpropanoid nature, such as cinnamic acid derivatives and several C-15 (C6-C3-C6)-skeleton-based flavonoids ^[16][17][18][55,56,57]. The halophytes accumulate phenolics and flavonoids at higher levels than other plants growing in areas of normal salinity and water conditions ^[16][19][55,58]. However, the presence of phenolic contents in the halophytes depends on the strength of the salinity in their growing environment ^[20][21][59,60]. Halophytes are also a potential source of other secondary metabolites, including alkaloids, saponins, iridoids, sterols, terpenoids, volatile oils, and certain bitter principles ^{[10][22][23][24][25][26][27]}[49,61,62,63,64,65,66]. Such phytochemicals, in addition to phenolics and flavonoids, make these plants potential natural sources for newer structural templates, and reservoirs of new and novel molecules sought for the treatment of several diseases ^[22][28][29][61,67,68]. These molecules, new and known, are also the basis of the claimed bioactivities of these plants. The common and specific pharmacological activities that are claimed in ethnomedicines and other traditional sources are attributed to this diversity of compounds that form the contents of the ingested plants in their extracted, concocted, and other forms, which includes their use as such, and as the whole plant. The halophytes and other plants used in traditional medicines have served populations dwelling in far-reaching areas where modern medicine and its facilities have not penetrated. Halophytes have, for long time, been the crucial component of traditional herbal medicine, and in this capacity, they have also served the nomadic tribes in the Arabian desert ^{[22][28][30][31][32]}[61,67,69,70,71]. Nonetheless, the range of bioactivity of the halophytes covers a broader segment in disease amelioration, and includes plants showing anti-bacterial, anti-fungal, anti-cancer, and anti-viral properties ^{[29][33][34][35]}[68,72,73,74]. Halophytes are also used to treat chronic diseases of the liver, heart, and kidneys, including jaundice, hypertension, diabetes, renal insufficiency, and renal calculi, by local and nomadic tribes in various regions where they occur ^[28][29][33][67,68,72].

2. Traditional Uses of Different Halophytes in Cancers and Cancer-Related Symptoms

Medicinal plants have been used as part of complementary and alternative medicines for different cancer types ^[36][141]. More than 3000 plant species are known for their anticancer activity ^[37][38][142,143]. Halophytes, widely distributed in the Arabian desert, have been used in traditional medicine for disease prevention and treatment ^[29][39][68,144]. Certain halophytes have also been used against cancers and in the management of cancer symptoms ^[40][41][42][145,146,147]. However, published data reporting the ethno-medicinal uses of halophytes in cancer are very limited ^[33][43][72,148]. However, the Plantago species (Fleaworts, Plantains), Rubia cordifolia (Manjistha, Indian Madder), and Salicornia herbacea (Glasswort) are known medicinal halophytes used against cancers ^[39][144]. Moreover, the concentrated decoction of Peganum harmala (Harmel), Zizyphus lotus (Wild jujube), Asplenium ceterach L. (Rustyback), and Calendula arvensis L. (Field Marigold) have been reported for tumor management ^[40][41][145,146]. Seeds of Atriplex halimus (Saltbush) are also used by breast cancer patients in Algeria ^[42][147]. Several species from the halophytic genus Salsola have been used as a remedy for cancers in Chinese traditional medicine, which includes Salsola tragus (Russian-thistle), Salsola foetida (Zri-che, Ecchi, Ressal, Aghacel), Salsola baryosoma, and Salsola richteri (Kata-kara, Cherkez) ^[44][149]. The common use of these plants to manage and treat cancers in traditional medicines is an incentive for researchers to further investigate their constituents and examine their effects on various cancer cell lines, as well as their effects in vivo.

3. Evaluating Anti-Cancer Activities of Halophytic Plants Extracts

A considerable number of reports are available in which halophytic plant extracts and their fractions have been screened for cytotoxic and antiproliferative effects ^{[45][46][47][48][49]}[150,151,152,153,154]. Most of these reports evaluated the anticancer activity of plant extracts and fractions that were identified by liquid chromatography–mass spectrometry (LC–MS) and gas chromatography–mass spectrometry (GC–MS) ^[48][49][50][153,154,155] for the presence of the chemical constituents. Nuclear magnetic resonance (NMR) spectroscopy has also been used for identification and quantification of the chemical constituents and their compositions in the mixture ^[51][156]. Quantitative spectrophotometric analysis has also been conducted ^[49][52][154,157]. For instance, n-hexane, dichloromethane, methanol, and water extracts from the xero-halophytic species Reaumuria vermiculata have been phytochemically investigated and evaluated for their anticancer activity together with their anti-inflammatory and antioxidant effects ^[53][158]. The n-hexane and dichloromethane extracts had the highest cytotoxicity against A-549 lung carcinoma cells (IC₅₀ values of 17 and 23 µg/mL, respectively), while the methanol extract of the plant showed the highest quantities of phenolics and flavonoids ^[53][158], indicating that the non-polar constituents were responsible for the plant’s anticancer properties. Some studies also demonstrated the anticancer activity of whole-plant extracts. Mohammed, et al. ^[49][154] reported the anticancer activity of an aqueous alcoholic extract from Pulicaria undulata growing in Saudi Arabia. They found that the plant extract had a potent cytotoxic effect against several cancer cell lines, including MCF-7, K562, and PANC-1, with IC₅₀ values ranging from 519 to 1535 µg/mL. The extract also inhibited normal fibroblast cell growth at IC₅₀ values greater than 4000 µg/mL, indicating the high selectivity index for the cancer cell lines. According to the authors’ conclusions, the accumulation of polyphenols and flavonoids in the plant extract was responsible for the plant’s anticancer effects ^[49][154]. In addition, the anticancer activities of essential oil constituents of some of the halophytic plants have also been reported. For example, oils obtained from Mentha piperita growing in the Experimental Halophytes Growing Base at the Shandong Academy of Sciences, Jinan, China, exhibited cytotoxic activity in pulmonary carcinoma (SPC-A1, human, lung cancer), K562 (human, chronic myelogenous leukemia), and gastric cancer (SGC-7901, human, first isolated from surgically resected metastatic lymph node) cell lines with IC₅₀ values which ranged from 10.89 to 38.76 µg/mL ^[54][159]. In vitro and in vivo assays were used to investigate the chemopreventive impacts of halophytes. Six halophytes were also examined in vitro for their stimulation of NAD(P)H: quinone oxidoreductase-1 (NQO-1) in the hepatoma cells (Hepa-1c1c7) murine culture. The results revealed that Ferocactus herrerae, Aptenia cordifolia, Carpobrotus edulis, and Ferocactus glaucescens were the most active chemopreventive plants ^[55][160]. Tamarix gallica methanolic extract was demonstrated in vivo to have chemopreventive activity against liver cancers, induced by diethylnitrosamine and 2-acetylaminofluorene, which worked through restoring the detoxifying cellular antioxidant enzyme ornithine decarboxylase and DNA synthesis ^[56][161]. Several investigations on other halophytes have been conducted in similar fashion with the purpose of identifying the plant components and quantifying the presence of key secondary metabolites and their cytotoxic activity (Table 1). The isolation, purification, and characterization of pure secondary metabolic ingredients from plant extracts involve time-consuming, technically advanced and difficult work in chromatographic and spectroscopic processes that lead to structure elucidations of the isolated pure compounds. Furthermore, the isolation techniques may not provide sufficient quantities of pure chemicals for undertaking in vivo and in vitro biological and pharmacological evaluations. Computer-assisted in silico receptor binding has paved the way towards a better understanding of the binding process and its requirements in energy and geometry of the ligand and the host protein through which the chosen compound exerts its biological functions ^[82][83][187,188]. In silico applications together with LC–MS and/or GC–MS analyses have revealed the particular protein involved in cancer development and activation of the substrate responsible for the cancer onset. The technique has been used to investigate the anticancer mechanisms of various plant-extract-based components ^[84][85][189,190]. In vitro and in silico experiments on the anticancer activities of particular enzymes from halophytic plant-extract compounds are reviewed ^[48][86][87][153,191,192]. The cytotoxic effects of Zygophyllum coccineum aqueous ethanolic extract on three cancer cell lines, MCF-7, HCT-116, and HepG2, have been explored. An in vitro suppression of human topoisomerase-II enzyme, and the in silico receptor-site binding by major compounds of Z. coccineum are also reported ^[48][153]. The results showed that the Z. coccineum extracts may have potential anticancer activity, as supported by the higher inhibition scores of the major constituents of the plant against human topoisomerase-II (IC₅₀ value 45.05 ng/mL) in comparison to the standard enzyme inhibitor staurosporine (IC₅₀ value 135.33 ng/mL). The binding energy requirements, obtained through in silico experiments, substantiated the findings ^[48][153]. Another example of in silico predictions involving the methanol extract compounds of Moricandia sinaica shoot have shown potential for cytotoxic activity, thereby corroborating the approach. In parallel, a GC–MS analysis identified 2-tridecen-1-ol as the major component in M. sinaica methanolic extract for higher binding energy of M-phase inducer phosphatase 2 (CDC 25 B) in comparison to the M-phase inducer phosphatase 1 (CDC 25A), which also suggested a plausible molecular mechanism for the extract’s anticancer effects ^[88][193]. Recent studies also demonstrated that Suaeda vermiculata extracts exhibit anticancer activity in HepG2 and HepG-2/ADR resistant cell lines. The plant extracts also improved the sensitivity of the HepG-2/ADR cells to doxorubicin, a known anti-cancer compound, which was evidenced by the in vitro MTT assay using combinations of the extracts with doxorubicin. The in silico binding affinity for the three ATP-binding cassette proteins responsible for the efflux of chemotherapeutic agents also indicated in this direction ^[89][194].

4. Isolated-Purified Anti-Cancer Agents from Different Halophytes

Anticancer activities as anti-proliferative and cytotoxicity of halophytic plant extracts have been widely studied; nonetheless, the anticancer activity of pure chemical compounds isolated, purified, and characterized from halophytes (Figure 2) is less encountered. Flavonoids, the most extensively distributed class of compounds in halophytes, have also been evaluated for their antitumor activity. For example, luteolin, vitexicarpin, and artemetin have been isolated from the halophyte Vitex rotundifolia and tested for their anticancer activity ^[90][195]. Among the three compounds, vitexicarpin was the most active cytotoxic agent against human gastric adenocarcinoma (AGS) and human colon cancer HT-29 cell lines, with IC₅₀ values of 6.9 and 22.8 µM, respectively. Vitexicarpin also induced apoptosis by upregulating the expression of TP53 and p21 and downregulating the expression of Bcl-2 at a concentration of 25 µM ^[90][195]. Catechin, epicatechin, and procyanidin B5 were isolated from Carpobrotus edulis and shown to possess cytotoxic activity against MDR1-transfected mouse lymphoma (L5178) cells, with IC₅₀ values equal to 12, 6, and 13 mg/L of the pure compounds, respectively ^[61][166]. In addition, three triterpenoids and a monogalactosyl diacylglycerol compound isolated from the same plant demonstrated antiproliferative potential in MDR1-transfected L5178 cells. In addition, uvaol (triterpene) exhibited the highest relative fluorescence factor (FAR) value and considerable inhibition of P-glycoprotein ^[61][166]. Halophytes are also a rich source of phenolic acids since they abundantly produce phenolics as a defensive mechanism against the oxidative stress of salinity. Therefore, phenolics have been represented in all reported phytochemical analyses of halophytes. In addition, some reports have investigated the isolation and anticancer effects of halophyte phenolics. For example, several phenolics have been isolated from Tamarix nilotica, including stamarixinin A (ellagitannin), gallic acid, methyl gallate, and 3,4-di-O-methylgallic acid, and these products have been examined for their antiproliferative activity against lung adenocarcinoma cell lines A549 ^[91][196]. Among these four compounds, gallic acid exhibited the highest cytotoxic effect, with an IC₅₀ value of 10.5 µg/mL. Other classes of natural products have also been identified from halophytes and found to exhibit anticancer activity. For instance, bitter principles of the furanocoumarin-type, i.e., bergapten, isopimpinellin, xanthotoxin, and imperatorin, as well as polyacetylene alcohols, i.e., panaxydiol, falcaindiol, and falcarinol, were isolated from Glehnia littoralis, a halophytic species, and were shown to have dose-dependent antiproliferative effects against HT-29 cell lines. Among all of the isolated compounds, falcaindiol was the most active cytotoxic agent against HT-29, with an IC₅₀ of 35 µM ^[69][174]. The pure alkaloid bocconoline, isolated from Glaucium flavum, demonstrated strong cytotoxic effects against MDA-MB-231 cell lines, with an IC₅₀ of 7.8 µM ^[92][197]. Juncunol (7-vinyl-9,10-dihydro-1,6-dimethylphenanthren-2-ol) was isolated from Juncus acutus ether extract, and exhibited potential cytotoxic activity against HepG2, HeLa, and MDA-MB-468, with IC₅₀ values ranging from 13 to 20 µM together with a highly selective index compared to its effect on the normal cell lines mTEC and S17 ^[93][198]. Finally, Salicornia herbacea polysaccharide inhibited cell growth and induced apoptosis in HT-29 cell lines ^[76][181]. The mechanisms by which these polysaccharides exhibit their anticancer activity has been attributed to their effectiveness in inducing G2/M cell cycle arrest at a dose of 4 mg/mL and the inhibition of cyclin B1 and Cdc2 mRNA, which leads to inhibition of HT-29 cell-line proliferation ^[76][181].