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History/Introduction
Research on the cytotoxic and anticlastogenic activities of the Cyclamen genus has been limited. In the 1950’s and 1960’s little research was done on the toxic saponin cyclamin, but no further investigation has recently been performed[1]. Cyclamin, a triterpenoid pentasaccharidic saponin, has previously been extracted from different Cyclamen species, including Cyclamen mirabile (Çaliş et al., 1997), Cyclamen trocopteranthum (Mihci-Gaidi et al., 2010), Cyclamen libanoticum (El Hosry et al., 2014) and Cylamen persicum (El Hostry et al., 2014).

Structure and Reactivity
As can be seen in Figure 1, cyclamin consists of a part with five connected tetrahydropyran rings with hydrophilic hydroxyl groups attached. The second part of the cyclamin molecule consists of a non-polar, sterol-like backbone. These two different parts make that cyclamin molecules, and saponins in general, are highly amphipathic compounds [Z]. However, the exact mechanism of action of cyclamin has not been extensively researched. The structure-activity relationship (SAR) of cyclamin and the other saponins is not yet known [A].

The partly hydrophobic and hydrophilic structure of cyclamin makes the compound permeable through the membrane. The carbohydrate part of saponins is water-soluble, making them surface-active [1]. Cyclamin is also known as a white opaque substance that absorbs up to 45% water and becomes transparent. Furthermore, it is soluble in alcohol and turns brown when exposed to light. When dissolved in water, it produces foam by frothing test and upon heating it has the unique property of coagulation. Concentrated sulfuric acid colors cyclamin in purple red, which disappears with water addition [4].

Available forms
Cyclamin can be extracted from Cyclamen plants such as the species mirable and trocopteranthum. Cyclamen are known houseplants; this raises concerns about the awareness of the toxicity of this flower. The xenobiotic cyclamin belongs to the family of triterpene saponins, which are derived from the saponin structure [3]. Triterpenoid compounds contain one or more sugar moieties attached to triterpenoid aglycones [2]. The large diversity of structures causes saponins to exhibit a wide range of biological and pharmacological properties. In China, cyclamin has been used as a traditional medicine for years [1]. Cyclamen has been used against menstrual disorders, digestive disorders, and anxiety in women [X]. But this is only the case for the leaves, the roots of the plants are known to be harmful if ingested [X2]. In these roots, cyclamin is found, as well as in the bulbs [X3]. Therefore, cyclamin is suspected to be the compound which causes the toxicity of these roots and bulbs in cyclamen plants.

Mechanism of action
Not much is known about the mechanism of action of cyclamin. However, a study proposed possible mechanisms of action based on their experimental results. Firstly, cyclamin might activate the proteins caspase-3, caspase-8 and caspase-9. Secondly, cyclamin could be responsible for increasing the expression levels of the cyclic-dependent kinase 2 and the cell division cycle 25 homolog A. Thirdly, cyclamin could increase the ratio of Bax/B-cell lymphoma 2 expression. Another property that was found is that cyclamin increases the permeability of Bel-7402 cells. This might be the reason why cyclamin enhances the effect of some chemotherapeutical drugs (Li et al, 2014).

Indications and symptoms
The roots of cyclamen plants are known to cause nausea, vomiting and diarrhea. Cyclamin is an irritant compound that causes gastroenteritis, bloody stools, dizziness, seizures and even death by asphyxiation. Studied by many physiologists, cyclamin was viewed merely as a local irritant [4]. However, considering the toxic effects of cyclamin, this a misconception. The roots and bulbs of cyclamen plants containing cyclamin are known to cause severe diarrhea and even death if eaten raw[5].

Adverse and side effects
The side effects of cyclamin have so far been reported to be beneficial. Cyclamin its working against proliferation and apoptosis of liver cancer cells [6]. Furthermore, its antibacterial and antifungal effects have been reported [4]. However, considering cyclamin is known to cause severe diarrhea and even death if eaten, more research needs to be done in order to use cyclamin as a possible liver cancer medicine for example.

Applications
Cyclamin is used as an ingredient for a nasal spray to reduce the tension of the wall and induce secretion of mucous (Relats, 2013). Furthermore, due to its toxic effects on different (cancer) cell types, cyclamin might be considered for use as chemotherapeutic drug. However, more research first has to be done to reduce its toxicity on normal human cells (El Hosry et al, 2014).

Toxicological data
In a study, cyclamin was tested regarding its toxicity against several types of cancer cells: SK-BR-3, HT-29, HepG2/3A, NCI-H1299, BXPC-3, 22RV1 but also on its toxicity against human normal fibroblasts DMEM, which are not cancer cells (El Hosry et al, 2014). The results showed that cyclamin induced a significant increase of micronucleated cells after it was activated through metabolism. This means that heritable chromosome mutations could occur in these cells. This result was observed in all cell types that were analysed in this study, therefore including the fibroblasts. The toxicity was indicated by the IC50 value which gives the concentration of the compound at which it causes 50% of its inhibitory effect e.g. on enzymes in cells (Ugwu & Conradie, 2023). The IC50 values of cyclamin were very similar across the different cell types, ranging from 0.32µM – 0.84µM, with the lowest IC50 value in the human normal fibroblasts DMEM cells, which indicates unspecific toxicity of cyclamin across different cell types (Table 1). This indicates that cyclamin is more toxic to the human fibroblasts compared to its toxicity against cancer cell lines. Compared to the chemotherapeutic drug mitomycin C, which has IC50 values ranging from 0.45µM-20.20µM in the cancer cell lines, cyclamin was up to 50 times more toxic for certain cell types when comparing the IC50 values (Table 1). The antioxidant activity of cyclamin was also determined. Cyclamin had an EC50 value of 0.96mM which indicates low antioxidant activity compared to reference compounds catechin (EC50 = 0.009 mM) and ascorbic acid (EC50 = 0.014 mM) (El Hosry et al, 2014). The EC50 value represents the potency of a compound by stating the half-maximum concentration of the compound with regards to its concentration where it causes maximum response or effect (Singh et al, 2020). Furthermore, it seemed that cyclamin did not have an anticlastogenic effect in the tested cell lines (El Hosry et al, 2014).

Another study found that cyclamin was less toxic to human colorectal cancer cells, from that type HTC 166 and HT-29, compared to the chemotherapeutical drug paclitaxel (Mihci-Gaidi et al, 2010). This could be concluded from the results that cyclamin had higher IC50 values compared to paclitaxel (Table 2).

To conclude, cyclamin shows broad toxicity against several cancer cell types, which would make it a promising drug to be used in that respect (El Hosry et al. 2014). However, its toxicity against normal human cells should be investigated further before using it as basis for chemotherapeutic drug to reduce unwanted side effects. Only then it can be decided if cyclamin is suitable for such a medical use.

Effects on animals
Cyclamin has not been thoroughly investigated in terms of its effects on animals, given it is not a widely known compound. However, the effects of Cyclamin on the snail Biomphalaria glabrata (Say) in terms of molluscicidal activity were researched. The lowest concentration showing 100 % mortality to snails was 21 mg/l [5].