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Review

Squirting Cucumber, Ecballium elaterium (L.) A. Ritch: An Update of Its Chemical and Pharmacological Profile

by
Attilio Anzano
,
Bruna de Falco
,
Laura Grauso
and
Virginia Lanzotti
*
Department of Agricultural Sciences, Università di Napoli Federico II, Via Università 100, 80055 Portici, NA, Italy
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(18), 4377; https://doi.org/10.3390/molecules29184377
Submission received: 27 July 2024 / Revised: 27 August 2024 / Accepted: 12 September 2024 / Published: 14 September 2024
(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery, 2nd Edition)
Browse Figures
Versions Notes

Abstract

:
Ecballium elaterium, also known as squirting cucumber, is a plant which is widespread in temperate regions of Europe, Africa and Asia. The plant is considered to be one of the oldest used drugs. In the last decades, E. elaterium has been widely studied as a source of triterpene metabolites named cucurbitacins, often found as glycosylated derivatives, used by the plant as defensive agents. Such metabolites exhibit several biological activities, including cytotoxic, anti-inflammatory, and anti-cancer. Interestingly, the bioactive properties of E. elaterium extracts have been investigated in dozens of studies, especially by testing the apolar fractions, including the essential oils, extracted from leaves and fruits. The purpose of this review is to provide an overview of the chemical profile of different parts of the plants (leaves, flowers, and seeds) analyzing the methods used for structure elucidation and identification of single metabolites. The pharmacological studies on the isolated compounds are also reported, to highlight their potential as good candidates for drug discovery.

1. Introduction

Ecballium elaterium (L.) A. Rich., is a herbaceous plant belonging to the Cucurbitaceae family that grows in the Mediterranean area, and which is the only one belonging to the Ecballium genus. It is commonly named squirting cucumber or exploding cucumber, for the ability of the fruit to violently disperse the seeds (from the Greek, εκβαλλω = to expel, to cast out). When the fruits reach a certain degree of ripening, or when an animal grabs the fruits and separates them from the stem, the internal pressure (up to 27 atm) throws the seeds away from the plant, allowing the plant to rapidly colonize wide areas. E. elaterium is native to Mediterranean areas, but it can be also found in northern Africa countries and temperate regions of Western Asia. It is considered an invasive species, as it can easily grow in rich soils and sunny environments, but it can grow in poor and drained soils too; it does not need much water, nor a specific pH range. Very recently Motti et al. (2023) documented the presence of this plant in the Ansanto Valley (Avellino province, Southern Italy) [1]. This finding is very interesting, since that place, named Mefite, can be considered a peculiar ecological niche, due to boiling mud lakes and vents with very high levels of natural CO2 emissions [1]. The plant grows as a perennial herb with wide, hairy, dark green and rough leaves, hairy and green stems that can grow up to 0.3 m, green, oval and hairy fruits, and pale yellow flowers that flourish between June and August (Figure 1) [2,3]. The small, dark brown, round seeds can be found inside the fruit, together with the fruit juice, which is the main part known for both beneficial and harmful properties. In traditional medicine, the dried fruit juice, called “elaterium”, has been used to treat rheumatism, jaundice, sinusitis, fever, liver disorders, and constipation, especially in medicine in Tunisia, Algeria and Turkey, and today it is still used in some Mediterranean medicinal sistems [1,4,5,6,7]. Recent studies on the plant fruits, seeds and roots extracts confirmed these biological activities. The beneficial properties of the fruit juice have been widely studied, and are attributed to the cucurbitacins, a class of tetracyclic triterpenes mainly found in Cucurbitaceae, but also to other bioactive components of the plant [8].
Several cucurbitacins have been isolated over the last years, ten of which have been identified in E. elaterium. Cucurbitacins can also be found as glycosides with different monosaccharides, mainly d-glucose and l-rhamnose, but these molecules are much less studied, and little is known about their effects on living organisms [9]. The fruit and the fruit juice are also known to be toxic for humans and animals if eaten, because of the high quantity of active principles contained in the juice, which can lead to severe damage, such as accelerated pulse, nervousness, dyspnea, anorexia, diarrhea, and, in some extreme cases, death by convulsions and asphyxia [9]. Salhab provided a list of medical cases in which exposure of people to the E. elaterium juice led to edema at a nasal, pharynx or uvular level, throat soreness, shortness of breath, conjunctivitis, and cardiac and renal failure [10]. These consequences are caused mainly by the high content of cucurbitacins, which are heavy purgatives and have a strong bitter taste. The first cucurbitacin was extracted from E. elaterium, attaching importance to this plant that is not edible and which is toxic, and thus it was less important than the other edible Cucurbitaceae. In fact, the concentration of cucurbitacin in E. elaterium, around 3.84% w/w (weight per weight) in the fruits, 1.34% in the stems and 0.34% in the leaves, ref. [11] is considerably higher than in other edible Cucurbitaceae, where the cucurbitacin content is usually between 0.1 and 0.3% and, anyway, below 1% [9,12]. Because of this, E. elaterium is considered a good source of cucurbitacins, and in some cases it has also been cultured in vitro with the aim of producing cucurbitacins [9]. This, together with the many different biological activity possessed by different parts of the plant, make this plant quite important from the chemical and pharmacological point of view.
Recently, Ielciu et al. wrote a review about E. elaterium and Bryonia alba highlighting the main characteristics of these two plants belonging to the Cucurbitaceae family [13]. Other than this study, no other recent review works can be found specifically about E. elaterium. The scientific literature regarding this plant is relatively poor, especially concerning the chemical composition of the different parts of the plant. The purpose of this review work is to provide an overview of the chemical profile of E. elaterium leaves, seeds and fruits in order to give an overview of all the molecules that have been identified up to now. The biological activities reported for the different plant extracts are also reviewed, as well as the pharmacological studies on the isolated cucurbitacins, to highlight their potential as good candidates for drug discovery.

2. Chemical Composition of the Plant Leaves, Fruits and Seeds

The different parts of the plant have been studied to determine their chemical composition and to find the role of such metabolites in the plant. Table 1 lists all the metabolites extracted and characterized to date, based on the very different chemical structure belonging to the main classes of fatty acids, carbohydrates, alkanes, esters, aldehydes, tocopherols, terpenes and their derivatives, flavonoids, and phytohormones.
Comparison of the chemical profiles evidenced differences in the chemical composition of the different parts of the plant. In particular, terpenes and volatiles were reported from leaves, along with flavonoids, phenolics and sugars. Triterpenoids, based on the oleanoic acid structure, were detecetd in the plant fruits. Unsaturated fatty acids and steroids were reported in seeds.
Table 1. Chemical composition of Ecballium elaterium leaves, fruits and seeds.
Table 1. Chemical composition of Ecballium elaterium leaves, fruits and seeds.
CompoundsFormulaChemical StructureQuantityRef.
LeavesFruitsSeeds
Benzaldehyde (1)C7H6OMolecules 29 04377 i00112.3% of total area 1,2--[2]
Benzeneacetaldehyde (2)C8H8OMolecules 29 04377 i0020.9% of total area 1,2--[2]
β-Bisabolol (3)C15H26OMolecules 29 04377 i0030.7% of total area 1,2--[2]
Butyl cyclohexyl phthalate (4)C18H24O4Molecules 29 04377 i0041.3% of total area 1,2--[2]
Cubitene (5)C20H32Molecules 29 04377 i0051.2% of total area 1,2--[2]
β-Cyclocitral (6)C10H16OMolecules 29 04377 i0060.8% of total area 1,2--[2]
β-Damascone (7)C13H20OMolecules 29 04377 i0071.1% of total area 1,2--[2]
n-Decanal (8)C10H20OMolecules 29 04377 i0081.5% of total area 1,2--[2]
4,6-Dimethyl-3,5,7- trioxatetracyclo [7.2.1.0(4,11).0(6,10)] dodecane (9)C11H16O4Molecules 29 04377 i0091.1% of total area 1,2--[2]
6-Ethyl-3-octyl isobutylester phthalic acid (10)C22H34O4Molecules 29 04377 i0100.8% of total area 1,2--[2]
Ethylsorbate (11)C8H12O2Molecules 29 04377 i0110.8% of total area 1,2--[2]
cis-Eudesma,6,11 diene (12)C15H24Molecules 29 04377 i0120.9% of total area 1,2--[2]
Eudesmol (13)C15H26OMolecules 29 04377 i0131.0% of total area 1,2--[2]
10-epi-γ-Eudesmol (14)C15H26OMolecules 29 04377 i0142.1% of total area 1,2--[2]
α-Fenchocamphorone (15)C9H14OMolecules 29 04377 i0152.0% of total area 1,2--[2]
Germacrene A (16)C15H24Molecules 29 04377 i0160.7% of total area 1,2--[2]
Hexadecanoicacid, methyl ester (17)C17H34O2Molecules 29 04377 i0172.8% of total area 1,2--[2]
Hinesol (18)C15H26OMolecules 29 04377 i01817.2% of total area 1,2--[2]
(E)-β-Ionone (19)C13H20OMolecules 29 04377 i0197.8% of total area 1,2--[2]
2-Isobutylthiazole (20)C7H11NSMolecules 29 04377 i0201.6% of total area 1,2--[2]
Isolongifolene (21)C15H24Molecules 29 04377 i0211.9% of total area 1,2--[2]
epi-Laurenene (22)C20H32Molecules 29 04377 i0221.3% of total area 1,2--[2]
Longifolol (23)C15H26OMolecules 29 04377 i0230.7% of total area 1,2--[2]
2-Methyl-7-octadecyne (24)C19H36Molecules 29 04377 i0242.6% of total area 1,2--[2]
E-Nerolidol (25)C15H26OMolecules 29 04377 i0251.2% of total area 1,2--[2]
Neryl acetone (26)C13H22OMolecules 29 04377 i0262.5% of total area 1,2--[2]
Nonadecane (27)C19H40Molecules 29 04377 i0271.5% of total area 1,2, 0.9% of total area 11.4% of total area 1-[2]
Safranal (28)C10H14OMolecules 29 04377 i0281.4% of total area 1,2--[2]
o-Tolualdehyde (29)C8H8OMolecules 29 04377 i0290.8% of total area 1,2--[2]
Vestitenone (30)C12H18OMolecules 29 04377 i0301.4% of total area 1,2--[2]
p-Vinylguaiacol (31)C9H10O2Molecules 29 04377 i0312.1% of total area 1,2--[2]
(24S)-Ethyl-5α-cholesta-7,22,25-trien-3β-ol (32) Molecules 29 04377 i0320.4mg/g of dry leaves--[14]
1-Allyl-1-but-3-enyl-1-silacyclobutane (33)C10H18SiMolecules 29 04377 i0331.51% of total area 2--[15]
Carvacrol (34)C10H14OMolecules 29 04377 i0346.09% of total area 2--[15]
3,4-Dimethylheptane (35)C9H20Molecules 29 04377 i0353.25% of total area 2--[15]
(E)-5-Eicosene (36)C20H40Molecules 29 04377 i0366.51% of total area 2--[15]
n-Hentriacontane (37)C31H64Molecules 29 04377 i03773,97% of total area 2--[15]
Limonene dioxide (38)C10H16O2Molecules 29 04377 i0387.61% of total area 2--[15]
Linolenic acid methyl ester (39)C19H32O2Molecules 29 04377 i0391.04% of total area 2--[15]
Loliolide (40)C11H16O3Molecules 29 04377 i0401.66% of total area 2--[15]
Neophytadiene (41)C20H38Molecules 29 04377 i0414.89% of total area (Hexane extract) 2--[15]
n-Pentacosane (42)C25H52Molecules 29 04377 i0421.75% of total area 2--[15]
7,10-Pentadecadiynoic acid (43)C15H22O2Molecules 29 04377 i0434.00% of total area 2--[15]
Phytol (44)C20H40OMolecules 29 04377 i0443.59% of total area 2--[15]
Propylhexedrine (45)C10H21NMolecules 29 04377 i0451.29% of total area 2--[15]
l-2-Tetramethyhexadecen-1-ol 3,7,11,15- (46)C20H40OMolecules 29 04377 i0461.16% of total area 2--[15]
Thymol (47)C10H14OMolecules 29 04377 i04712.05% of total area 2--[15]
(E)-Anethol (48)C10H12OMolecules 29 04377 i048-31.6% of total area 1-[16]
Dibuthylphtalate (49)C16H22O4Molecules 29 04377 i0490.5% of total area 13.2% of total area 1-[16]
3-(6,6-Dimethyl-5-oxohept-2-enyl)-cyclohexanone (50)C15H24O2Molecules 29 04377 i05020.4% of total area 18.8% of total area 1-[16]
Eicosane (51)C20H42Molecules 29 04377 i0511.9% of total area 12.7% of total area 1-[16]
Estragol (52)C10H12OMolecules 29 04377 i052-0.7% of total area 1-[16]
Henicosane (53)C21H44Molecules 29 04377 i0531.2% of total area 12.8% of total area 1-[16]
Heptadecane (54)C17H36Molecules 29 04377 i0541.3% of total area 12.1% of total area 1-[16]
Hexadecane (55)C16H34Molecules 29 04377 i0552.5% of total area 15.2% of total area 1-[16]
Hexahydrofarnesyl acetone (56)C18H36OMolecules 29 04377 i05619.1% of total area 12.1% of total area 1-[16]
Isobutylphthalate (57)C12H14O4Molecules 29 04377 i0571.0% of total area 11.7% of total area 1-[16]
Limonene (58)C10H16Molecules 29 04377 i058-0.8% of total area 1-[16]
Methylheptadecane (59)C18H38Molecules 29 04377 i0590.3% of total area 1--[16]
Nor-pristane (60)C18H38Molecules 29 04377 i0600.4% of total area 1 -[16]
Octadecane (61)C18H38Molecules 29 04377 i0612.9% of total area 15.7% of total area 1-[16]
Octylhexanoate (62)C14H28O2Molecules 29 04377 i0620.8% of total area 1--[16]
Octyloctanoate (63)C16H32O2Molecules 29 04377 i06330.0% of total area 13.5% of total area 1-[16]
Pentadecane (64)C15H32Molecules 29 04377 i0640.3% of total area 1--[16]
Phytene (65)C20H40Molecules 29 04377 i0651.3% of total area 1--[16]
Pristane (66)C19H40Molecules 29 04377 i0660.8% of total area 11.5 % of total area 1-[16]
p-Propylanisole (67)C10H14OMolecules 29 04377 i067-8.2% of total area 1-[16]
Tetracosane (68)C24H50Molecules 29 04377 i0683.7% of total area 17.4% of total area 1-[16]
Tetradecane (69)C14H30Molecules 29 04377 i0690.3% of total area 10.8% of total area 1-[16]
β-Thujone (70)C10H16OMolecules 29 04377 i070-3.0% of total area 1-[16]
Tricosane (71)C23H48Molecules 29 04377 i0712.0% of total area 14.9% of total area 1-[16]
Caffeoylglucaric acid (72)C15H16O11Molecules 29 04377 i072---[17]
Catechin (73)C15H14O6Molecules 29 04377 i073---[17]
Catechin-3-O-rutinoside (74)C27H34O15Molecules 29 04377 i074---[17]
Colocynthoside B (75)C42H62O15Molecules 29 04377 i075---[17]
4-Feruloylquinic acid (76)C17H20O9Molecules 29 04377 i076---[17]
9-/ or 13-Hydroxy-9Z,11E-octadecadienoic acid (77)C18H32O3Molecules 29 04377 i077---[17]
Linolenic acid (78)C18H30O2Molecules 29 04377 i078---[17]
Procyanidin dimer (79)C30H26O12Molecules 29 04377 i079---[17]
Shikimic acid hexoside isomer I (80)C13H20O10Molecules 29 04377 i080---[17]
Shikimic acid hexoside isomer II (81)C13H20O10Molecules 29 04377 i081---[17]
3,7,3′,4″-Tetrahydroxyflavanone (82)C15H12O6Molecules 29 04377 i082---[17]
7,3′,4′-Trihydroxyflavanone (83)C15H10O5Molecules 29 04377 i083---[17]
Trihydroxyflavanone-O-deoxyhexosyl-O-hexoside (84)C27H34O15n.d.---[17]
Trihydroxy-octadecadienoicacid (85)C18H32O5Molecules 29 04377 i084---[17]
Trihydroxy-octadecenoicacid (86)C18H34O5Molecules 29 04377 i085---[17]
Elateroside A (87)C42H66O14Molecules 29 04377 i086-0.3 mg/kg fresh fruit-[18]
Elateroside B (88)C48H78O18Molecules 29 04377 i087-2 mg/kg fresh fruit-[18]
3-O-β-d-Glucopyranosyl-3β-hydroxyolean-12-en-28-oic acid 28-O-β-d-glucopyraonoside (89)C42H67O13Molecules 29 04377 i088-3 mg/kg fresh fruit-[18]
Oleanolic acid 3-O-β-d-glucopyranoside (90)C36H58O8Molecules 29 04377 i089-5 mg/kg fresh fruit-[18]
Oleanolic acid 3-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside (91)C42H68O13Molecules 29 04377 i090-2 mg/kg fresh fruit-[18]
Arachidic acid (92)C20H40O2Molecules 29 04377 i091--0.84% of total fatty acid[19]
δ-5-Avenasterol (93)C29H48OMolecules 29 04377 i092--16.44 mg/100 g[19]
δ-7-Avenasterol (94)C29H48OMolecules 29 04377 i093--93.81 mg/100 g[19]
Campesterol (95)C28H48OMolecules 29 04377 i094--139.63 mg/100 g[19]
δ-7-Campesterol (96)C28H48OMolecules 29 04377 i095--19.18 mg/100 g[19]
Desmosterol (97)C27H44OMolecules 29 04377 i096--8.89 mg/100 g[19]
Linoleic acid (98)C18H32O2Molecules 29 04377 i097--48.64% of total fatty acid[19]
Myristic acid (99)C14H28O2Molecules 29 04377 i098--0.09% of total fatty acid[19]
Oleic acid (100)C18H34O2Molecules 29 04377 i099--15.58% of total fatty acid[19]
Palmitic acid (101)C16H32O2Molecules 29 04377 i1003.36% of total area2-4.09% of total fatty acid[19]
Puninic acid (102)C18H30O2Molecules 29 04377 i101--22.38% of total fatty acid[19]
Sitostanol (103)C29H52OMolecules 29 04377 i102--21.29 mg/100 g[19]
β-Sitosterol (104)C29H50OMolecules 29 04377 i103--396.25 mg/100 g[19]
Stearic acid (105)C18H36O2Molecules 29 04377 i104--4.93% of total fatty acid[19]
δ-7-Stigmastenol (106)C29H50OMolecules 29 04377 i105--86.68 mg/100 g[19]
Stigmasterol (107)C29H48OMolecules 29 04377 i106--6.29 mg/100 g[19]
α-Tocopherol (108)C29H50O2Molecules 29 04377 i1073.51% of total area 2-3.62 mg/100 g[19]
β-Tocopherol (109)C28H48O2Molecules 29 04377 i108--1.82 mg/100 g[19]
γ-Tocopherol (110)C28H48O2Molecules 29 04377 i109--44.23 mg/100 g[19]
δ-Tocopherol (111)C27H46O2Molecules 29 04377 i110--12.44 mg/100 g[19]
Cycloeucalenol acetate (112)C32H52O2Molecules 29 04377 i111---[20]
Fructose (113)C6H12O6Molecules 29 04377 i11232% of total sugars--[21]
Glucose (114)C6H12O6Molecules 29 04377 i11334% of total sugars--[21]
Inositol (115)C6H12O6Molecules 29 04377 i11413% of total sugars--[21]
Raffinose (116)C18H32O16Molecules 29 04377 i1157% of total sugars--[21]
Sucrose (117)C12H22O11Molecules 29 04377 i11614% of total sugars--[21]
N-Ethyl-l-asparagine (118)C6H12N2O3Molecules 29 04377 i11766.7mg/kg fresh areal parts--[22]
Phytomelin (119)C27H30O16Molecules 29 04377 i1188.54 mg/g of dry leaves1.84 mg/g of dry fruit-[23]
1 = Essential oils, 2 = aerial parts, n.d. = not defined.
The non-polar extracts are the fractions with most of the interesting compounds, from a chemical and pharmacological point of view. Touihri et al. characterized the hexane extract of E. elaterium seeds, using Soxhlet extraction and obtaining fatty acids, linoleic acid (98) being the most abundant one (48.64%), tocopherols, with a high presence of γ-tocopherol (110) (44.23 mg/100 g of seed oil), and phytosterols, with β-sitosterol (104) being the most abundant phytosterol (396.25 mg/100 g of seed oil) [19]. Hexane extracts from aerial parts of this plant were studied by Molavi et al., who found a very high content of n-hentriacontane (37) (73.97% of the volatile components) [15]. Many studies focused on essential oils extracted from different plant tissues. The analysis of Jebara et al. focused on essential oils from aerial parts of E. elaterium, resulting in 31 different polar and non-polar compounds identified and quantified, and showing that hinesol (18), benzaldehyde (1) and β-ionone (19) were the main components of the essential oils (17.2%, 12.3% and 7.8%) [2]. Moreover, essential oils were extracted from plant leaves and fruits by Razavi and Nejad-Ebrahimi, who found a relatively high quantity of anethol (48) (31.6%), in fruits, and of octyloctanoate (63) and 3-(6,6-Dimethyl-5-oxohept-2-enyl)-cyclohexanone (50) (30% and 20.4%, respectively), in leaves [16].
The polar extracts of E. elaterium tissues are, on the other hand, less studied, compared to the non-polar component. Akinci and Losel characterized the soluble sugar content of the leaves from different Cucurbitaceae, including E. elaterium, and the analysis highlighted a high content of glucose (114) and fructose (113) (34% and 32% of the total sugar composition, respectively) [21].

3. Cucurbitacins: Chemical Structure

Cucurbitacins are a class of tetracyclic triterpenes produced from plants belonging to the Cucurbitaceae family and thus isolated from E. elaterium (120–131, Figure 2). They are usually found in plants as glycosides, hydrolyzed by the enzyme elaterase during the extractive procedures, and releasing the aglycone part [9]. E. elaterium is the plant from which the first cucurbitacin, named α-elaterin, was isolated back in 1831. This compound has been later been renamed as cucurbitacin E (123). The main function of these secondary metabolites is to protect the plant against external attacks of herbivores, thanks to their strong bitter taste. The basic skeleton of cucurbitacins is a core structure of cucurbitane (19-(10→9β)-abeo-10α-lanost-5-ene), which is then oxygenated and substituted with acetyl groups affording the different cucurbitacins (Figure 2). The main differences among the chemical structures are related to the double bonds at C-1 and C-23, and the presence of a hydroxyl or acetoxyl group at C-25. Other differences concern the glycosilation at C-2 and the closure of a further ring (ring E).
These compounds are extracted by using apolar aprotic solvents, e.g., chloroform, dichloromethane, petroleum ether, benzene, and ethyl acetate, but are also soluble in protic polar solvents such as methanol and ethanol. Strucure elucidation is obtained by spectroscopic methods, including MS, 1H-NMR, and 13C-NMR. Over the years, the research on cucurbitacins produced a wide literature on their extraction, which included different methods and involved the use of various solvents. Cucurbitacins are moderately polar compounds, which are soluble in organic solvents. They have been reported in the plant fruit. The aglycone is poorly soluble in water and highly soluble in chloroform [9]. The most-used solvents for the extraction of E. elaterium fruits, as shown in Table 2, were chloroform and dichloromethane, but also methanol, ethanol and petroleum ether, by using Soxhlet extraction, or solvent maceration of the dried fruit powder or fruit juice, under stirring.
The purification steps were usually performed by silica gel chromatography using the low polarity of these molecules to carry out multiple purification steps. In more recent works, the use of HPLC coupled with a UV detector is more commonly adopted, using acetonitrile, methanol and water as mobile phases, and coupled with UV as the detector.
Further information about the chemical structures of cucurbitacin were obtained by using spectroscopic techniques, including 1H-NMR, 13C-NMR and MS (Table 2). Furthermore, Sturm and Stuppner developed a method to simultaneously analyze the cucurbitacins present as aglycones and the glycosylated ones, using a precise HPLC-MS method [24]. The two glycosylated cucurbitacins analyzed in the work of El Sayed and Badr were extracted from the whole plant, using a 90% ethyl alcohol solution, purified by silica gel chromatography, and structurally elucidated through 1H-NMR [6].
In the studies that we considered, after the identification of the cucurbitacins, the authors rarely proceeded with quantification. The purification, identification and quantification processes are long and tedious, and the cucurbitacins are usually purified after multiple fractionation steps. The only studies that quantified cucurbitacins are the ones by Agil et al. [25], Yesilada et al. [26], Tosun and Baysar [27], Seger et al. [28], and El Sayed and Badr [6], as shown in Table 2.
Table 2. List of cucurbitacins found in Ecballium elaterium extracts and their correlated biological activity.
Table 2. List of cucurbitacins found in Ecballium elaterium extracts and their correlated biological activity.
NameChemical FormulaMolecular Mass (g/mol)Plant PartExtraction SolventMethodQuantityBiolological ActivityRef
Cucurbitacin A (120)C32H46O9540.70FruitHexaneHPLC-DAD-ESI-MS--[17]
Cucurbitacin B (121)C32H46O8558.70FruitPetroleum etherSilica gel chromatography,IR, 1H-NMR, 13C-NMR2.56% of the fruit juiceAnti-hepatotoxic effect in mice[25]
---n.a.Antimicrobial activity against S. aureus, antiviral activity against HSV-1[8]
FruitDichloromethaneHPLC-MS, 1H-NMR, 13C-NMRn.a.-[28]
LeavesMethanolLC-ESI-MSn.a.Cytotoxic effect, inhibition of human glioma cell adhesion[29]
FruitFruit juicePreparative TLC
1H-NMR		2.57 mg crude/g dry juiceAnti-inflammatory activity induced by cucurbitacin B in mice[26]
Dihydro-Cucurbitacin B (127)C32H48O8560.72FruitHexaneHPLC-DAD-ESI-MS--[29]
Cucurbitacin D (122)C30H44O7516.67FruitMethanol, ethanolHPLC-ESI-MSn.a.Decrease bilirubin level in human plasma[5]
---n.a.Inhibition of lung cancer cell proliferation[30]
FruitMethanolColumn chromatography1H-NMRn.a.Cytotoxic effect on gastric cancer cells[31]
FruitDichloromethaneHPLC-DAD-MS, 1H-NMR, 13C-NMRn.a.-[32]
FruitDichloromethaneHPLC-MS, 1H-NMR, 13C-NMR6 mg-[28]
FruitWaterHPLC-UV, 1H-NMR, LC-ESI-MS86.4 µg/g of dried residue-[27]
FruitHexaneHPLCn.a.Cytotoxic, apoptotic, and anti-migration effects against hepatocellular carcinoma[33]
22-Deoxo-Cucurbitacin D (128)C30H46O6502.33FruitDichloromethaneHPLC-MS, 1H-NMR, 13C-NMR37 mg (mixture with Cuc. R)-[28]
FruitDichloromethaneHPLC-DAD-MS, 1H-NMR, 13C-NMRn.a.-[32]
(23S, 24Z)-16,23-Epoxy Cucurbitacin D (129)C30H44O6500.67FruitDichloromethaneHPLC-MS, 1H-NMR, 13C-NMR3 mg-[28]
Cucurbitacin E (123)C32H44O8556.69FruitChloroformHPLC-DAD-UVn.a.Cytotoxic effect on Parkinson’s disease cells[34]
---n.a.Cytotoxic effect, immunostimulant effect[35]
---n.a.Cytotoxic effect on breast carcinoma cancer cells, melanoma and prostate adenocarcinoma[36]
Fruit--n.a.Cytotoxic effect on ovarian cancer cells[4]
FruitMethanolHPLC-UVn.a.-[37]
FruitMethanolColumn chromatography1H-NMRn.a.Cytotoxic effect on gastric cancer cells[31]
FruitDichloromethaneHPLC-MS, 1H-NMR, 13C-NMRn.a.-[28]
FruitDichloromethaneHPLC-DAD-MS, 1H-NMR, 13C-NMRn.a.-[32]
FruitHexaneHPLCn.a.Cytotoxic, apoptotic, and anti-migration effects against hepatocellular carcinoma[33]
2-O-β-d-Glucopyranosyl Cucurbitacin E (130)C38H54O13718.36Whole plant90% Ethyl alcoholSilica gel chromatography,1H-NMR46.67 mg/kg fresh plant-[6]
Cucurbitacin I (124)C30H42O7514.65FruitMethanol, ethanolHPLC-ESI-MSn.a.-[5]
FruitChloroformColumn chromatography1H-NMRn.a.Cytotoxic effect on gastric cancer cells[31]
FruitDichloromethaneHPLC-MS, 1H-NMR, 13C-NMRn.a.-[28]
FruitDichloromethaneHPLC-DAD-MS, 1H-NMR, 13C-NMRn.a.-[32]
FruitWaterHPLC-UV, 1H-NMR, LC-ESI-MS61 µg/g of dried residue-[27]
FruitHexaneHPLC-UV, 1H-NMR, 13C-NMRn.a.Anti-cancer effect against hepatocellular cancer cells[38]
FruitHexaneHPLCn.a.Cytotoxic, apoptotic, and anti-migration effects against hepatocellular cancer cells[33]
FruitChloroformHPLC-UVn.a.Anti-cancer effects on breast cancer cells[39]
2-O-β-d-Glucopyranosyl Cucurbitacin I (131)C36H52O12676.35Whole plant90 % Ethyl alcoholSilica gel chromatography,1H-NMR34.67 mg/kg fresh plant-[6]
Cucurbitacin L (125)C30H44O7516.67FruitDichloromethaneHPLC-MS, 1H-NMR, 13C-NMRn.a.-[28]
Cucurbitacin R (126)C30H46O7518.68FruitDichloromethaneHPLC-MS, 1H-NMR, 13C-NMR37 mg (mixture with 22-Deoxo Cuc. D)-[28]
n.a. = not available, DAD = Diode Array Detector; ESI = Electron Spray Ionization; HPLC = High-performance Liquid Chromatography; HSV = Herpes Simplex Virus; IR = Infrared; NMR = Nuclear Magnetic Resonance; MS TLC = Thin-Layer Chromatography, UV = Ultraviolet.

4. Cucurbitacins: Biological Activity

Investigations on the potential biological activity of cucurbitacin has resulted in the identification of biological properties (Table 2). Figure 3 shows the number of studies on the biological activity (A) and the distribution of these activities within the single metabolite tested (B). Interestigly, cyctotoxic and apoptotic activities were found for cucurbitacin D (122), E (123) and I (124), while anticancer activity was observed for D (122) and I (124). Cucurbitacin D (122) decreased bilirubin, while E (123) was shown to be an immunostimulant. Studies on cucurbitacin B (121) showed cytotoxic, anti-hepatotoxic, antimicrobial and anti-inflammatory activity (Figure 3B).
However, it has been found that the oral, subcutaneous, intraperitoneal and intravenous supply of pure cucurbitacin in various animals produce severe toxicity. The adverse effects resulting from pure cucurbitacin administration can vary, from general disorders like accelerated pulse, dyspnea, anorexia, diarrhea, and irritation of mucosa, to severe conditions like convulsions, asphyxia, and accumulation of fluids in organs, with the consequent organ failure and death. The most toxic cucurbitacins are cucurbitacins D (122) and I (124), with an LD50 (Lethal Dose 50) value of 5 mg/kg of body weight in mice. Both cucurbitacins have an unsaturated side chain and a free hydroxyl group, differing in a double bond at C-1 [9].
Going into detail in the tested biological activities, cucurbitacin B (121), extracted from E. elaterium fruits, was found to possess anti-hepatotoxic effects in mice, by Agil et al. [25]. Later on, Hassan et al. performed antimicrobial and antiviral tests of pure cucurbitacins B against Staphylococcus aureus and against the virus HSV-1, and confirmed the antimicrobial activity of this molecule [8]. The group of Yesilada et al. tested cucurbitacin B (121) in mice to assess the anti-inflammatory activity of this principle, finding an activity threshold of 50 mg/kg of mouse body weight [26]. Cucurbitacin D (122) was found to reduce the bilirubin level in human plasma by Greige-Gerges et al. [5], and was found to inhibit the proliferation of gastric cancer cells in the work of Jacquot et al. [30]. Moreover, Üremiş et al. isolated and tested cucurbitacin I (124) against hepatocellular cancer cells, and demonstrated the anti-cancer effect of the substance [38]. This finding adds up to the activity against breast cancer cells reported by Yılmaz and Deniz for cucurbitacin I (124) [40]
The most observed effect of cucurbitacins was the cytotoxic effect. Touihri-Barakati et al. found that cucurbitacin B (121) exerted cytotoxicity against human glioma cells, reducing their adhesive ability, as well [29]. Cucurbitacin D (122) cytotoxicity was tested against gastric cancer cells from Jafargholizadeh et al. [31] and against hepatocellular carcinoma by Üremiş et al. [33]. Additionally, cucurbitacin E (123) exhibited cytotoxic activity in many works, against Parkinson’s disease cells, against ovarian cancer cells, breast carcinoma cells, melanoma, prostate adenocarcinoma and hepatocellular carcinoma [4,31,33,34,36]. Finally, some works highlighted cucurbitacin I (124) cytotoxic activity against gastric cancer cells, hepatocellular cancer cells and breast cancer cells [31,33,39].

5. Biological Activity of Different Plant Tissues

E. elaterium has been used for more than 2000 years as a medicinal plant to treat several conditions such as rheumatism, jaundice, sinusitis, fever, liver disorders, constipation, hypertension, and cirrhosis [4,5,6,41]. Thus, starting from these traditional uses, many articles have tested the extracts from different parts of the plant and documented various biological activities. Table 3 reports all the biological and pharmacological studies available in the literature, with particular attention on the tested extract, the observed effect and target organism, and the tested concentration.
Antibacterial and antimicrobial activities were demonstrated for different extracts against Klebsiella pneumoniae, Salmonella typhi, Staphylococcus aureus, Candida albicans, Bacillus subtilis, Salmonella enteritidis in many articles that focused on chloroform, hexane, ethyl acetate, butanol, ethanol, aqueous and methanol fruit extracts [42,43,44,45]. The reason why these extracts can exert such activity is still under investigation, but Elkhateeb et al. [43] showed that the E. elaterium nanoparticles used in their study could break the cellular membrane of S. typhi, while Felhi et al. [45] concluded that the methanol extract they used was bacteriostatic against Gram-positive bacteria and bactericidal against Gram-negative bacteria, due to the difference in the membrane composition.
Several studies explored the anti-inflammatory activity against different types of diseases, suggesting that the content of cucurbitacins and the different polyphenols in E. elaterium parts could have a protective role against inflammation. Again, the extracts that exhibited anti-inflammatory activity were the fruit extracts and the fruit juice extracts, probably because of the cucurbitacin content, as shown in the article of Yesilada et al., which tested the extracts against mice, and isolated cucurbitacin B (121), correlating the anti-inflammatory activity with this metabolite [26]. Demir et al. [41] demonstrated the efficacy of fruit ethanolic extract against sepsis-induced lung injury, while Heysieattalab and Sadeghi [46] used fruit juice to reduce neuroinflammation in rats. Moreover, ethanol and methanol fruit extracts were used against inflammation of nasal mucosa and inflammation due to carrageenan-induced paw edema in rats [47]. An anti-inflammatory activity of E. elaterium fruit ethanol extract against sepsis-associated encephalopathy and fruit juice against liver fibrosis have been investigated by the groups of Arslan et al. [48] and Ghanim et al. [49], finding the fruit extracts effective in both cases.
Table 3. Biological activity of Ecballium elaterium extracts from the different plant tissues.
Table 3. Biological activity of Ecballium elaterium extracts from the different plant tissues.
ActivityMaterial TestedPlant PartDiseaseObserved Effect and Target OrganismQuantityRef.
AntibacterialHexane, chloroform, ethyl acetate, butanol, ethanol extractsFruit-Antibacterial effect against 10 K. pneumonia strainsMIC: 32–64 µg/mL[42]
Anti-fibrotic80% ethanol extractFruitFibrosisReduced fibrosis, wound healing in rats5 mg/kg of body weight[50]
Anti-inflammatoryAqueous extractFruitRhinosinusitisAnti-inflammatory activity in white rabbits-[51]
80% ethanolic extractFruitSepsis-induced lung injuryAnti-inflammatory effect against sepsis-induced lung injury in rats2.5 mg/kg of body weight[41]
Fruit juiceFruitNeuroinflammationAnti-inflammatory activity in rats10.9 µg/kg body weight
21.8 µg/kg body weight		[46]
Fruit juice, dichloromethane extractFruitIncreased vascular permeability induced by HOAcAnti-inflammatory activity induced by cucurbitacin B in mice50 mg/kg of body weight[26]
Fruit juice, dichloromethane extractFruitIncreased vascular permeability induced by HOAcAnti-inflammatory activity induced by cucurbitacin B in mice50 mg/kg of body weight[26]
Fruit juice, ethanol extractFruitInflammation of the nasal mucosaAnti-inflammatory activity in rats100 mg/mL, 200 mg/mL and pure juice[47]
Methanol extractFruitCarrageenan-induced hind-paw edemaAnti-inflammatory activity in rats75 mg/kg[45]
80% ethanol extractFruitSepsis-associated encephalopathyAnti-inflammatory activity in rats2.5 mg/kg[48]
Fruit juiceFruitLiver fibrosisAnti-inflammatory activity and hepatoprotective effect in mice100 mg/kg of body weight[49]
AntimalarialHexane extractRoot-Antimalarial effect determined by beta-hematin testMIC: 4.645 mg/mL[52]
Dichloromethane extract-MIC: 2.637 mg/mL
Methanol extract-MIC: 0.124 mg/mL
Dichloromethane extractSeed-MIC: 1.338 mg/mL
Methanol extract-MIC: 0.458 mg/mL
Hexane extractFruit-MIC: 3.518 mg/mL
Dicloromethane extract-MIC: 3.641 mg/mL
AntimicrobialAqueous extractFruit-Antimicrobial activity against S. typhiMIC: 10 µg/mL[43]
80% ethanol extractFruit-Antimicrobial effect against S. aureus and C. albicansMIC between 0.195 and 1.563 mg/mL for S. aureus strains and between 0.097 and 6.250 mg/mL for C. albicans[44]
Methanol extractFruit-Antimicrobial activity in S. aureus, B. subtilis, K. pneumonia, S. enteritidisMIC: 6 mg/mL (B. aureus, B. subtilis), 12 mg/mL (K. pneumonia, S. enteritidis)[45]
Antioxidant90% ethanol extractFruit-Antioxidant activityIC50: 3.57 mg/mL[53]
Methanol extractFruit-Antioxidant activity156 μg/mL[45]
Anti-tumoursSeed oilSeedGliomaReduced adhesion of glioma cell lines (U87 cell lines) to fibrinogen (IC50 = 9.2 µg /mL), fibronectin (IC50 = 34.1 µg /mL).Adhesion to fibrinogen (IC50 = 9.2 µg/mL), to fibronectin (IC50 = 34.1 µg/mL)[29]
AntiviralFruit juiceFruit-Antiviral activity against BRV/ERU_2018 strain-[3]
CytotoxicAqueous extractFruit-Cytotoxic actiovity against AGS and KYSE30 cancer cell linesIC50: 2.5, 0.7, 0.7 μg/mLfor AGS cells after 24, 48, 72 h.
IC50: 500, 150, 125 μg/mL after 24, 48, 72 h for KYSE30 cells		[54]
80% ethanol extractSeed-Cytotoxic activity against MA-104 cell lineLogIC50: 6.03[3]
90% ethanol extractFruit-Cytotoxic activity against cancerous cell linesIC50: between 1.953 and 702 μg/mL[53]
Fruit juiceFruit-Cytotoxic activity against MA-104 cell lineLogIC50: 4.8[3]
Fruit juiceFruit-Cytotoxic and mutagenic effect against human blood cells72 µL/L for 48 h[55]
Fruit juiceFruit-Cytotoxic and genotoxic effect against A. cepa meristematic cells10, 20 and 50 mL/L and pure juice[56]
Intraperitoneal adhesion reduction80% ethanol extractFruitPostoperative peritoneal adhesionReduction of postoperative intraperitoneal adhesions in rats2.5 mg/kg of body weight[57]
Pro-apoptoticFruit juiceFruitCCl4-induced hepatotoxicityPro-apoptotic effect in rats0.7 mg/kg of body weight[58]
MIC = Minimum Inhibitory Concentration, IC50 = Half Maximal Inhibitory Concentration, BRV/ERU = Bovine Rotavirus strain.
Cytotoxic activity was studied both in vivo and in vitro. Fruit juice was cytotoxic against monkey kidney cells, human blood cells and A. cepa meristematic cells, according to the results of Aksoy et al. [3], Rencüzogullari et al. [55], and Çelik and Aslantürk [56]. Furthermore, aqueous and ethanolic extracts were tested against other type of cancer cell lines, demonstrating their cytotoxic activity [3,53,54].
Other works from different research groups showed that fruits, seeds and roots of E. elaterium are effective against other conditions. İbiloglu et al. showed that an amount of 5 mg/kg of ethanol fruit extract can reduce fibrosis and enhance wound healing in rats [50]. Asgharian et al. tested different extracts from roots, seeds and fruits, and found an antimalarial effect of all the fractions, with an MIC ranging from 0.124 mg/mL to 4.645 mg/mL, suggesting that the phenolic content of the extracts could be correlated with the antimalarial effect [52]. Touihri-Barakati et al. studied the anti-tumour effect of E. elaterium seed oil against glioma cells: the application of seed oil decreased the adhesion of the cells to fibrinogen and to fibronectin, reducing the possible metastasis, with the fatty acids such as linoleic acid (98), oleic acid (100), palmitic acid (101) and punicic acid being indicated as possible responsible of such results [29]. Anti-viral activity against a bovine rotavirus (BRV/ERU) was obtained after using fruit juice on the target virus [3]. Fruit juice also exerted a pro-apoptotic activity in the work of Naggar et al., when the juice was administrated to rats with a dose of 0.7 mg/kg of rat weight, suggesting that cucurbitacin B, as shown in Table 3, could be the molecule that was exerting the pro-apoptotic activity. [58] On the other hand, ethanolic extract of fruit in rats was able to reduce the postoperative intraperitoneal adhesions, formations that can lead to abdominal pain and intestinal obstruction [57].

6. Conclusions

The biological importance of E. elaterium, which explain its use as a remedy in traditional medicine, is mainly due to the cucurbitacin content, and only in a minor extent to other chemical constituents found in the extracts from different plant parts. In this review, we brought to attention the chemical, physiological, and biological characteristics of this plant, which has not been very much studied in the past years. Future studies should investigate and clarify the molecules responsible for some of the tested biological activities, still not clarified today, and determine whether or not such in vivo and in vitro activities are ascribable to the isolated cucurbitacins. Also, some efforts could aim to fill the lack of information and knowledge about the glycosylated cucurbitacins and, eventually, clarify their positive and negative effects.

Author Contributions

Conceptualization, V.L. and L.G.; methodology, A.A.; software, A.A. and B.d.F.; validation, B.d.F. and L.G.; data curation, A.A.; data analysis, A.A. and L.G.; writing—original draft preparation, A.A.; writing—review and editing, V.L.; supervision, V.L.; funding acquisition, V.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the PSR-GAL “Irpinia, Sannio, Cilsi” project. Misura 16 “Cooperazione”. Tipologia di Intervento 16.1.1 Azione 2: Sostegno ai Progetti Operativi di Innovazione (POI).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data will be provided by the authors, on request.

Acknowledgments

We would like to thank Luigi Zollo for his skillful project management.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 04377 g001
Figure 1. Ecballium elaterium leaves and flowers (A), fruits (B), and seeds (C).
Figure 1. Ecballium elaterium leaves and flowers (A), fruits (B), and seeds (C).
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Figure 2. Chemical structure of cucurbitacins isolated from Ecballium elaterium leaves and fruits.
Figure 2. Chemical structure of cucurbitacins isolated from Ecballium elaterium leaves and fruits.
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Figure 3. Biological activity exhibited by E. elaterium cucurbitacins (A) and the distribution of these activities within the single metabolite tested (B).
Figure 3. Biological activity exhibited by E. elaterium cucurbitacins (A) and the distribution of these activities within the single metabolite tested (B).
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Anzano, A.; Falco, B.d.; Grauso, L.; Lanzotti, V. Squirting Cucumber, Ecballium elaterium (L.) A. Ritch: An Update of Its Chemical and Pharmacological Profile. Molecules 2024, 29, 4377. https://doi.org/10.3390/molecules29184377

AMA Style

Anzano A, Falco Bd, Grauso L, Lanzotti V. Squirting Cucumber, Ecballium elaterium (L.) A. Ritch: An Update of Its Chemical and Pharmacological Profile. Molecules. 2024; 29(18):4377. https://doi.org/10.3390/molecules29184377

Chicago/Turabian Style

Anzano, Attilio, Bruna de Falco, Laura Grauso, and Virginia Lanzotti. 2024. "Squirting Cucumber, Ecballium elaterium (L.) A. Ritch: An Update of Its Chemical and Pharmacological Profile" Molecules 29, no. 18: 4377. https://doi.org/10.3390/molecules29184377

APA Style

Anzano, A., Falco, B. d., Grauso, L., & Lanzotti, V. (2024). Squirting Cucumber, Ecballium elaterium (L.) A. Ritch: An Update of Its Chemical and Pharmacological Profile. Molecules, 29(18), 4377. https://doi.org/10.3390/molecules29184377

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