What do steroidal saponins do

Certain pathologies associated with immunocompromised diseases as opportunistic fungal infections have been treated with the steroidal saponins C, which are composed of a C aglycone moiety and a sugar chain with one or more monosaccharides [ 8 ]. This response could be the reason that saponins are capable of inducing a nonspecific immune response having an immunomodulatory activity by stimulating both cell-mediated and humoral immune responses [ 24 ].

The SC-2 saponin is a potent antimycotic [ 25 ]. An important biological function of saponins is their capacity to induce cell death by means of programmed or nonprogrammed routes. The effect that these compounds exert inside the tumor cell has been widely evaluated, providing evidence that they could be used as agents to control cell proliferation. Steroidal saponins derived from Withania somnifera L.

Dunal Ashwagandha have shown antiproliferative activity in rat C6 glioma cell lines [ 26 ]. Saponins can act at different cellular levels and are capable of forming pores in lipid bilayers increasing the cellular permeability, thus enabling the uptake of molecules that would otherwise be excluded and produce toxic stimuli [ 27 ]. The toxic activity shown by saponins has allowed them to be considered as possible therapeutic agents, but it is important to contemplate the possible side effects caused by their toxicity, since drugs have a dual effect; i.

Recent reports suggest that some saponins exhibit antiproliferative and apoptotic activity and act selectively without presenting cytotoxicity [28—32].

These findings are generating great interest in these compounds as therapeutic agents for treating cancer. Cancer includes a group of complex genetic diseases that affect aged cells. Carcinogenesis is a multi-step molecular process induced by genetic and epigenetic changes that disrupt the balance between cell proliferation, apoptosis, differentiation, senescence, and the pathways that control these cellular processes see review in [ 33 ].

Different types of programmed cell death are known, including apoptosis and autophagy Figure 5. Both processes are complex and are regulated by different enzymatic activities. Apoptosis is morphologically characterized by cellular shrinkage, DNA fragmentation, and the formation of cellular fragments surrounded by a cytoplasmic membrane termed apoptotic bodies [ 34 ].

The enzymatic activity in apoptosis is developed by the caspases that are the proteases responsible for the morphological changes [ 35 ]. Autophagic cell death is characterized by an exacerbated formation of autophagic vesicles and an increased lysosomal activity [ 36 , 37 ]. The hallmark of the programmed cell death processes is the absence of an immunologic response that takes place in the accidental cell death known as necrosis. Characteristics of the necrosis, apoptosis, and autophagic cell death.

Each cell death has its own morphological and biochemical properties. Numerous studies using in vitro and in vivo models have been conducted to evaluate the antitumor activity of various saponins Figure 6 , including triterpene and steroidal saponins and diosgenin. Different cancer types have been treated with plant extracts that have a high quantity of steroidal saponins, as well as with isolated or synthetic steroidal saponins.

In vitro and in situ assays to evaluate the antitumor activity of saponins inside different types of cancer. Several such assays have used plant extracts in different tumor cells. A recurrent model in the evaluation of steroidal saponins is the hepatocellular carcinoma cells HepG2. It has been shown that in the extract obtained from Asparagus officinalis L. Steroidal saponins isolated from Paris polyphylla Sm.

Several strategies have been used to control cancer cell proliferation, including inducing cell death or cytotoxic effect on cancer cells; however, new strategies could be planned to allow more efficient chemotherapy treatments. Steroidal saponins from Trillium tschonoskii Maxim. In colon cancer cells, the anticancer effect of several plants containing saponins has been observed inside human colon cancer cell lines.

Allium flavum L. A , which suppresses cell growth in Caco2 and SW human colorectal cancer cell lines in two ways: by arresting the cell cycle and by inducing apoptosis [ 43 ]. Breast cancer is one of the most common malignancies in women and the second leading cause of cancer deaths [ 44 ]. It has been proposed that this cytotoxic property may be due to the presence of saponins, triterpenes, tannins, and polyphenolic compounds in the extract [ 54 ].

Tor et al. The biological activity of Fagonia indica Burn. The antitumor effect of saponins has also been demonstrated in ovarian cancer cell lines. The principal constituents of Rhizoma Paridis a stem of Paris polyphylla Sm. PSII has shown an antitumor effect in ovarian cancer cells, and studies have demonstrated that it achieved its effect by activating several mechanisms, including cell-cycle arrest and apoptosis [ 47 ].

The antitumor effect of saponins in lung cancer has been reported in both in vivo and in vitro models. The immunomodulatory role of the steroidal saponins obtained from P. These steroidal saponins induce apoptosis cell death in A lung cancer cells.

Intense research into the anticancer effects of steroidal saponins has led to the discovery of new compounds whose properties could be improved. Researchers have isolated compounds that have been used individually or in combination to induce cell death in different cancer type cells. The steroidal saponin tupichinin A, together with seven known compounds isolated from rhizomes of Tupistra chinensis Baker, showed potent cytotoxicity against the cancer cell lines HL, SMMC, A, MCF-7, and SW [ 50 ], while the mixed saponins balanitin-6 and -7 showed anti-tumor activity in both in vivo and in vitro systems [ 51 ].

This is evidence of the broad range and the various mechanisms of action of saponins. Some steroidal saponins have been extensively evaluated such that each compound has an antitumor effect on different cancer types, and examples of this are dioscin and diosgenine Figure 7. Structures of dioscin and diosgenin. Diosgenin is an aglycone of steroidal saponins that exhibits antiproliferative and pro-apoptotic activities on cancer cells in vitro. Cancer metastasis involves the migration of cancer cells from the primary tumor.

In this process, the matrix metalloproteinases are the main proteases that participate in tumor cell migration, spreading, tissue invasion, and metastasis [ 53 ]. Multiple studies have demonstrated the role of diosgenin as an anticarcinogenic factor, and have shown that diosgenin was able to inhibit metastasis in vitro in human prostate cancer PC-3 cells [ 54 ].

No clear correlation between the burrs morphology and the chemical composition of the samples has been found. Abstract The steroidal saponins of Tribulus terrestris L.

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A vast structural diversity of Allium spirostanols is associated with the differences in the structure of aglycones, especially their oxygenation patterns and stereochemistry Table 1. However, a double bond located at C25 27 was reported in the aglycones of saponins present in A. The C methyl group is found with either S or R absolute configuration. In many cases the isolated sapogenins appear to be a mixture of diastereomers R and S. Until now, over spirostanol glycosides have been identified in various Allium species.

Allium spirostane-type saponins are typically monodesmodic with the sugar residue usually at C-3 position. In rare cases, the sugar moiety was reported to be linked at other positions, such as C-1 e. Table 3 of ESM summarizes chemical structures of spirostane-type saponins that were reported in Allium species. In the case of furostane-type sapogenins a double bond may also be located at 20 22 e. The Me group may be in either R or S configuration. From among furostanol glycosides identified in the Allium genus, sixteen compounds were found to be such methoxy-derivatives.

Furostanol saponins in Allium plants are bidesmodic glycosides with sugar chains attached usually at C-3 and C positions. A vast majority of furostanol saponins possess an O-linked glucose residue attached at position C A review of available literature data shows that as much as 18 cholestane-type compounds have been identified in ten different Allium species.

Sugar units are attached at one, two or, more seldom, at three separate positions in A. Most of these compounds are glycosylated at C, whereas in contrast to spirostanol and furostanol saponins, the attachment of sugar chain at position C-3 is almost unique tuberoside U [ ] Sang et al. Plant names are cited exactly as they were referred to in the original report.

It is almost certain that some of them are synonyms but as the authors of the present review are not specialists in plant taxonomy no amendments have been made.

Saponins are considered responsible for numerous pharmacological properties of many plants, and they are recognized as active constituents of Allium species as well.

It should be mentioned, however, that Allium plants are not rich sources of these compounds. Results from quantitative studies indicate that saponin content is usually very low, for example A.

Quantitative densitometric determination of diosgenin—the main sapogenin of A. A significant exception, in terms of saponin content, is A.

It should be emphasized however that the results from many pharmacological in vitro and in vivo studies revealed several interesting activities of Allium saponins, for example antifungal, cytotoxic, antispasmodic, hypocholesterolemic, and other.

Cytotoxic activity of saponins was discussed in a number of experimental papers on Allium species. Amongst tested spirostane saponins dioscin [ ], isolated from A. This compound, which is widely distributed in species of the family Dioscoreaceae and Asparagaceae, revealed significant in vitro activity in tests performed on many other cancer cell lines Podolak et al.

Some authors claim that apart from the type of the cell line, the structure of the oligosaccharide chain, especially the site of interglycosidic linkages, rather than the sapogenin, are the modulating factors of cytotoxic properties Rezgui et al. These results corroborate with those obtained by Mimaki et al. The most potent spirostanol glycosides include also eruboside B [ 79 ], leucospiroside A [ 97 ], yayoisaponin C [ 95 ] and aginoside [ 93 ] isolated from A.

The two latter compounds, that were isolated from A. Tigogenin pentasaccharide [ 67 ] A. Several spirostanol glycosides, that were isolated from different Allium species, revealed fairly high cytotoxic activity in tests on promyelotic leukemia cells HL Yuccagenin tetrasaccharide karatavioside A [ ] from the bulbs of A.

Tuberoside M [ ] from the seeds of A. Other compounds isolated from this latter species were considered to be inactive. The authors concluded that the presence of an additional OH group at C-6 in gitogenin skeleton is detrimental to activity, while cholestane glycosides showed no effect. In accordance with the studies of Mimaki et al. Opposite results were obtained however with two cholestane glycosides isolated from A. Results of cytotoxicity assays of several spirostanol sapogenins indicated their weak activity or lack of it.

Agigenin [ 34 ], porrigenin A [ 38 ] and porrigenin B [ 23 ] identified in A. However, some of the steroidal glycosides isolated from the same plant exhibited quite a good activity towards J and WEHI cells, the most active being gitogenin and porrigenin C derivatives IC 50 ranging from 1. From among tested furostanoles the majority of compounds showed weak activity or lack of it, for example two glycosides isolated from A.

Among numerous furostanoles obtained from A. The differences in activity between compounds having the same aglycone but differing in sugar chain was observed by Zolfaghari et al. Antifungal saponins require particular attention as there is a constant need for new agents that would be effective against opportunistic fungal infections and could provide an alternative to chemical fungicides used in the fight against plant pathogens.

Unfortunately, only a few studies have been performed so far on Allium steroidal glycosides. Antifungal activity of Allium saponins was modulated by both the sapogenin type and the number and structure of the sugar residue.

Generally saponins with spirostanol skeleton exhibited higher antifungal activity than furostanols. Yu et al. The results from in vitro assays against different plant and human pathogen strains are provided in Table 5 of ESM.

Studies by Barile et al. Minutosides A-C [ , , ] A. The most pronounced effect was seen with a spirostanol minutoside B [ ], as compared to both furostanols minutosides A [ ] and C [ ].

Persicosides A [ ] and B [ ]—compounds isolated from A. The antifungal activity of isolated compounds against B. Interestingly, all saponins inhibited the growth of P. Ceposides A-C [ , , ] isolated from A. The authors observed a significant synergism of action between those three saponins against B.

Ceposide B [ ] showed significant activity against all fungi with the exception of F. Ceposides A [ ] and C [ ] were active against all fungi with the exception of A. Agigenin 3- O -trisaccharide [ 90 ] and gitogenin 3- O -tetrasaccharide [ 73 ], isolated from the bulbs of A.

Voghiera, were more active against B. All the compounds were effective towards T. Mskhiladze et al. In another study the same compound isolated from A. Eruboside B [ 79 ] A. Agigenin glycosides: aginoside [ 93 ] together with yayoisaponins A [ 96 ] and C [ 95 ] isolated from A. Aginoside [ 93 ] at ppm completely inhibited the growth of C. The influence of the structure of the sugar chain on the observed anti-fungal activity of compounds bearing the same aglycone was revealed in studies by Teshima et al.

Alliospirosides A [ ] and B [ ] both 25 S -ruscogenin glycosides , which are present mainly in the basal plates and roots of A.

It was also more effective against M. Saponin fraction isolated from the methanol extract of A. Laxogenin glycosides exhibited significant activity only on cAMP phosphodiesterase, one of which, with an acetyl group in the saccharide moiety, was almost as potent as papaverine used as a positive control IC 50 3. Also, saponins isolated from A. In the same study, furostanol saponins were revealed to be much more potent than the corresponding spirostanol glycosides.

The results were in contrast to the previous studies of these authors which showed that furostanol glycosides were less active, exhibiting only weak inhibitory activity or none. The authors concluded that the anti-enzyme activity could be dependent on the number of hydroxyls in the A and B rings as in the present study the tested furostanol saponins contained several OH groups.

Saponins isolated from the fruits of A. Moreover, it was revealed that alliospirosides A [ ] and B [ ] were both uncompetitive enzyme inhibitors, while alliospiroside D [ ] — competitive. Drugs acting via inhibition of the activity of this transport enzyme may be of potential use in the treatment of many diseases of the cardiovascular system, the kidneys, the immune system, which are connected with disturbances in the active transport of ions.

Three saponins from A. Their activities were evaluated on H 2 O 2 -injured cardiac H9C2 cells. It was shown that glycosides exhibited less protective efficacy than sapogenins. Among these, laxogenin [ 6 ] and tigogenin [ 1 ] displayed stronger effects than furostane-type aglycones. The authors concluded that the presence of F ring in spirostanols may enhance their protective activity whereas oxidation in the B ring might be detrimental as laxogenin was less active than tigogenin.

Nine furostane saponins isolated by Lai et al. Cell viability was determined by MTT assay. Fistulosaponin A [ ] was the most effective compound with a cell viability of In animal studies, alloside B [ ], isolated from fruits of A. The cholesterol-lowering effect of garlic is probably partially due to the steroid saponin presence.

In a rat model of experimental hyperlipidemia induced by feeding a 0. It was claimed that the reduction of concentration of plasma cholesterol concentration is the result of inhibition of cholesterol absorption by saponins in the intestine or a direct effect on cholesterol metabolism. Apart from the agapanthagenin glycoside, all the tested compounds were able to reduce induced contractions, as measured by the reduction of histamine release, in a concentration-dependent manner.

The authors concluded that the positive effect is associated with the presence of a hydroxyl group at position C-5 and of a glucose unit at position C On the other hand, hydroxylation at C-6 and glucose attachment at C-3 seem to be structural features responsible for the loss of activity.

Furostane-type saponins that were isolated from A. Macrostemonoside A [ 65 ] increased the synthesis and release of visfatin in 3T3-L1 adipocytes and elevated mRNA levels in this cytokine in a dose- and time-dependent mode Zhou et al. The authors observed that the molluscicidal activity of isolated compounds increased with an increasing number of monosaccharides in a sugar moiety.

Aginoside [ 93 ] was found to be toxic to leek-moth larvae Acrolepiopsis assectella Harmatha et al. In this paper steroidal saponins reported in various Allium species from early to March are reviewed, including their skeletal structures and sugar chains.

Allium genus is characterized by a great diversity of structures. Apart from spirostane- and furostane-type compounds, a rare group of open-chain saponins has been identified in several species. Despite a relatively low content of steroidal glycosides in Allium species, they are considered to contribute, in addition to sulfur compounds, to the overall biological activity of these plants.

Undoubtedly, stability of saponins is their advantage as compared to fairly unstable sulfur compounds, thus, they in fact may be predominant active constituents of Allium products. Bearing this aspect in mind it seems highly feasible to develop antifungal Allium preparations against animal and plant pathogens. Also, reports on high in vitro cytotoxic activity of steroidal saponins from Allium species makes them potential candidates for further development as anti-cancer agents.

National Center for Biotechnology Information , U. Phytochemistry Reviews. Phytochem Rev. Published online Oct 8.