|Year : 2019 | Volume
| Issue : 5 | Page : 953-960
Frondoside A is a potential anticancer agent from sea cucumbers
Fatma Hussain Sajwani
Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain, UAE
|Date of Web Publication||4-Oct-2019|
Fatma Hussain Sajwani
P.O. Box 27055, Sharjah
Source of Support: None, Conflict of Interest: None
Cancer is a leading cause of death worldwide. Although high cure rates are achievable with current available drugs, this is not without side effects. Hence, attention has been shifted to alternative anticancer agents coming from natural products as treatment options. Extracts from marine sea cucumbers have been investigated for such properties. Frondoside A is a natural glycoside extracted from the sea cucumber, Cucumaria frondosa, which has been used as a traditional remedy, recently, the extract was found to have potential anti-tumor properties. This narrative review aimed at critically analyzing and summarizing the literature available regarding Frondoside A anticancer properties. For that, scientific databases such as PubMed, EMBASE, and ScienceDirect were searched for the keywords; Frondoside A, cancer, metastasis, anticancer properties, and sea cucumbers. Articles in languages other than English were excluded from the study. Such review will help researchers to better tailor future experiments and will enrich the knowledge about natural compounds consumed as traditional substances.
Keywords: Anticancer properties, cancer, Frondoside A, metastasis, pro-apoptosis
|How to cite this article:|
Sajwani FH. Frondoside A is a potential anticancer agent from sea cucumbers. J Can Res Ther 2019;15:953-60
| > Introduction|| |
Cancer is still considered a leading cause of death worldwide. Currently available chemotherapeutic agents are of high curative rates but not without side effects. Many such drugs act though inducing apoptosis in cancer cells.,
Sea cucumbers, scientifically known as “Holothuroidea,” are marine echinoderms, living on the floors of the oceans., Their shape ranges from spherical to elongated cucumber like, hence, the name. Cucumaria frondosa is one of the species from the Cucumaria genus, cucumariidae family in the dendrochirotida order of the Holothuroidea class. It is one of the largest sea cucumbers and the most common type in New England, it is also abundant in the North Atlantic Ocean and Russia's Barents Sea. C. frondosa is harvested, dried, and processed using segmented chromatography to extract multiple biologically active components. Many of which have been investigated for different possible pharmacological functions including anti-inflammatory, anti-bacterial, and immune-modulatory functions , as well as the anticancer effects in different types of cancer.
C. frondosa has been used as a dietary supplement , and a traditional remedy in old Chinese medicine. Yet, there have been 14 biologically active glycosides extracted from it. Frondoside A is a triterpenoid glycoside extracted from the skin of C. frondosa. Other forms of bioactive glycosides are available from other types of sea cucumbers, these include Frondoside A2-2, Frondoside A4-2, and Frondoside A7-1.
Structurally, Frondoside A consists of a pentaoside with one sulfate group. It has an aglycon ring with a xylose attached as a 3rd monosaccharide residue, 3-O-methylglucose as a terminal monosaccharide and an acetoxyl group at C-16 of the aglycon ring.,,,, [Figure 1] shows the structure of Frondoside A.
In the fast-growing field of cancer drug development from different natural products; this review aimed at providing researchers with an up-to-date knowledge on the anticancer properties of Frondoside A to guide them in future studies.
The scientific databases PubMed, EMBASE, and ScienceDirect were searched for the following terms: “Frondoside A,” “Sea cucumbers,” “Cancer” and “anticancer properties” in English. Articles in other languages were excluded. Full articles including original research papers as well as reviews were critically evaluated for the scientific content and summarized while conference presented abstracts were excluded from the study.
For cancer cells survival, they need to gain certain malignant phenotypes. These include maintaining continuous proliferation signals, avoiding normal growth suppressors, resisting apoptosis, manifesting unlimited replication abilities, inducing angiogenesis, and invading adjacent tissue in addition to the ability for distance metastasis. Most anticancer therapies available target one or more of these malignant phenotypes. Studies have shown Frondoside A to target multiple cancer cells characteristics making it an interesting potential compound to be used in cancer therapy. These studies are discussed in this paper and are summarized in [Table 1].
|Table 1: Summary of the studies that investigated the anti-cancer effect of frondoside A|
Click here to view
| > Cancer Growth Inhibition and Antiproliferation Properties|| |
Frondoside A inhibits cancer cell growth through multiple mechanisms. It causes decrease cell viability in many cell lines including human LNM35 lung cancer cells in a dose-dependent manner. Lung cancer growth suppression by Frondoside A was also confirmed in vivo.
Janakiram et al. examined Frondanol A5, a crude extract from C. frondosa consisting of other compounds in addition to Frondoside A, has shown its inhibitory effect on colon cancer in rat models. In human HCT116 colon cancer cell lines, frondanol A5 causes cell-cycle arrest at G2-M interphase. Giving frondanol A5 as a dietary supplement in adenomatous polyposis coli mouse model significantly decreased the development of small intestinal tumors and to a lower extend large intestinal polyps.,,
Frondoside A found to increase the expression of cyclin-dependent kinase inhibitor; p21. In a study where colon cancer was induced using azoxymethane, rats were treated with Frondanol A5 and analysis of the aberrant cryptic foci for p21 revealed increase expression in the treated group compared to the untreated.
In vitro testing on human prostate cancer cell lines (PC-3, DU145, VCaP. 22Rv1 and LNCaP) revealed Frondoside A to cause reduction in cell viability and colony formation, with androgen-sensitive tumor cell lines to be more sensitive to Frondoside A (IC50 ranged from 0.5–2 μM) compared to other cell lines. The same study has demonstrated cell-cycle arrest in response to the treatment for 48 h duration in PC-3 cell line but not in DU145.In vivo testing confirmed the in vitro results with significant tumor growth inhibition in xenograft models. The study reported no side effects in terms of stable hemoglobin and platelet count. No change in mice weight was observed and no signs of distress during treatment. In this study, the spleen was reported to be enlarged with higher concentration treatments. Lymphocytosis and monocytosis were seen in the treated group and this can be explained by the immune modulatory effects of Frondoside A.
In a study of Frondoside A effect on multiple Burkitt's lymphoma cell lines, Frondoside A inhibited cell viability after 48 h treatment with a concentration rage of 0.3–0.6 μM. Comparing this to the effect of Frondoside A in other solid tumors, the IC50 concentration in Burkitt Lymphoma was much lower than reported before.
| > Pro-Apoptosis Properties|| |
Multiple studies have shown its pro-apoptotic effect to be mediated through decrease expression of the anti-apoptotic proteins from the Bcl-2 family and increase in the pro-apoptotic proteins. In general, Frondoside A was found to activate the cysteine-aspartic proteases caspase 3/7 and 9 in multiple cancer cell lines.,,,
Li et al. demonstrated its effect in suppressing cancer cell proliferation in AsPC-1 human pancreatic cancer cell lines and inducing apoptosis demonstrated by increased annexin V positive cells after treatment. Proteins extracted from the treated cells were analyzed by western blot and showed increased bands corresponding to the active forms of caspases-3,-7, and -9. The activation of the apoptotic pathway was suggested to be p21 dependent. Treatment of human estrogen receptor-negative breast cancer cell line (MDA-MB-231) with different concentrations of Frondoside A for 24 h showed higher expression levels of p53 which was dose-dependent, and this was associated with increase in caspase-3/7 and 9 activity as well as caspase 8 to a lower extent. In this study, blocking caspase 3 with specific inhibitor was associated with absolute inhibition of apoptosis in the treated cells. This again confirms the caspase-dependent apoptosis induced by Frondoside A in this cell line. In human lung cancer cell lines LNM35, A549, and NCI-H460, apoptosis has been confirmed by increase cell population in sub-G1 fraction and was also mediated by the activation of the same caspases.
Protein analysis from human pancreatic cancer cell lines treated with the compound showed decreased anti-apoptotic proteins; Bcl-2 and Mcl-1 with increase in pro-apoptotic proteins such as Bax. Frondoside A was found to activate p53 in these cell lines. Frondoside A also downregulated the expression of Bcl-2 and survivin in Burkitt's lymphoma cell lines. This was associated with the release of cytochrome c from the mitochondria as well as the nuclear translocation of the apoptosis-inducing factor (AIF) with concomitant induction of apoptosis.
One study conducted in human myeloid leukemia cell lines including HL-60, NB-4, and THP-1 showed that apoptosis was induced in these cells after treatment with Frondoside A in a dose and time-dependent manner. Significant decrease in pro-caspases 3 and 7 expression on western blot and increase in cleaved caspase 3 and 7 was detected after 6 h of treatment. A corresponding change was seen in poly ADP ribose polymerase (PARP) expression. In this study, no change in mitochondrial membrane permeability was detected when HL-60 cells were treated and the level of cytoplasmic cytochrome c did not change which is essential for the activation of the intrinsic apoptosis pathway. In these cell lines, the apoptosis detected by annexin V was much earlier than the detection of activation of caspases, which suggests that the initiation of apoptosis was caspase-independent. To further investigate this, the author used different caspase inhibitors along with Frondoside A treatment and observed only partial inhibition of apoptosis. Similar experiments were conducted on other Holothuroidea glycosides (Frondoside A2-2 and A4-2) and complete block of apoptosis was detected with the use of the caspase inhibitors. From this study, it was concluded that Frondoside A activates apoptosis, at least initially, in a caspase-independent manner and alternative pathways might be involved. We can add to this that structurally different glycosides can vary in their functional characteristics since the apoptosis caused by the other compounds was caspase dependent. Similar finding was reported in a study on RT112 urothelial carcinoma cell line where Frondoside A-induced apoptosis was detected by annexin V, cleavage of procaspase 3, 9, and 8 as well as PARP. Using a pan-caspase inhibitor did not block the apoptosis induced by Frondoside A treatment, which suggests the process to be caspase independent. The study showed treatment with Frondoside A for 48 h to be associated with upregulation of the expression of cyclin-dependent kinase inhibitor protein, p21 and the pro-apoptosis protein Bax.
In Burkitt's lymphoma cell lines, Frondoside A also induced apoptosis in caspase-independent manner where the activation of caspase-3,-9 and the cleavage of PARP by Frondoside A was not inhibited by the use of the caspase-inhibitor; zVAD.
Dyshlovoy et al. showed that apoptosis pathway activated in prostate cancer in response to the treatment with Frondoside A is cell-type specific. In his study, apoptosis was caspase-dependent in DU145 cell line and caspase-independent in PC-3 and LNCaP. Protein expression analysis on western blot showed downregulation of antiapoptotic proteins such as Bcl-2. Upregulation of the pro-apoptotic protein PTEN was only demonstrated in the caspase-dependent cell line. All cell lines used in this study showed upregulation of p21, which confirms the compound's effect on cell-cycle control. Interestingly, Frondoside A treatment showed inhibition of survival autophagy in those prostate cancer cell lines. Inhibition of autophagy was confirmed in two other studies; on urothelial carcinoma cell lines  and Burkitt's lymphoma cell lines.
| > Anti-Invasive and Anti-Metastasis Properties|| |
Frondoside A has demonstrated its effect on inhibiting cancer cell invasion by decreasing the intracellular expression of matrix metalloproteinase 9 (MMP 9) which plays a vital role in breaching the extracellular matrix allowing cancer cells to invade adjacent tissue including blood vessels and lymphatics hence promoting cancer metastasis. This inhibition is mediated though the inhibition of PI3k/AKT, ERK1/2, and p53 MAPK pathways. It also increases the level of tissue inhibitor of metalloproteinase (TIMP 1 and 2).
Frondoside A was found to inhibit activator protein-1 and nuclear factor-κβ that are needed to bind the promoter region on MMP gene for activation. This effect was demonstrated in breast and lung cancers by wound healing and matrigel invasion assay., In lung cancer, the anti-invasion effect was seen at low concentrations of Frondoside A, so the author suggested that it is a specific effect on cell migration and not because of the decreased cell viability as a result of compound cytotoxicity.
A study on breast cancer metastasis has shown that pretreatment of breast cancer cells before injecting to mice models has led to 30% decrease in the tumor metastatic colonies to the lung, but it did not reach clinical significance. In another study, the decrease in lung metastasis from human 66.1 breast cancer cell line has been confirm. Injecting syngeneic Balb/cByJ mice with cancer cells that has been pretreated with 1.0 μM/L Frondoside A significantly suppressed the number of lung metastasis colonies (P < 0.0001) although the direct systemic treatment of the breast cancer mice model with Frondoside A in the same study did not reach clinical significance (P = 0.06).
The mechanism of metastasis inhibition involved in such breast cancer models was further investigated. Ma et al. showed decrease cAMP generation and hence blockage of ERK1/2 pathway in cells treated with Frondoside A as it antagonizes the effect of prostaglandin E-2 (PGE-2). Breast cancer cells were also found to inactivate NK-cells migration and cytokine release through PGE2 receptor 4 (EP4). Since Frondoside A has been shown to antagonize EP4; treatment with low doses were able to restore the function of the NK-cells which added to its contribution to the decrease in metastatic potentials. Prostate cancer metastasis to the lung in xenograft models was also found to be significantly reduced with the treatment of Frondoside A.
| > Anti-Angiogenic Properties|| |
Studies showed Frondoside A to have additional anti-angiogenic properties in lung cancer LNM35 xenografts, where it significantly inhibited angiogenesis. Studies have shown that the suppression of basic fibroblast growth factor induced new blood vessel formation by Frondoside A when used in nontoxic concentrations. This confirms that the observation of reduced vascularity in the tumor is due to specific compound effect and not due to cell apoptosis and death. The property might be contributing to its effect on reducing cancer growth and metastasis since the blood supply is vital for cell growth and can be a mode of influencing distant metastasis.
| > Effect of Frondoside a on Cancer Stem-Like Properties|| |
Cancer stem cells are thought to determine the behavior of the tumor including metastasis, relapse, treatment resistance, and it is thought that these cells are responsible for cancer growth. Breast cancer stem cells are characterized by the expression of colony-stimulating factor 1 (CSF-1), CSF-M, c-met, CXCL12, and CD44 cell markers. A study aiming at investigating the effect of COX-2 pathway and PGE 2 role in breast cancer by blocking PGE-2 receptor 4 (EP-4) using Frondoside A, which acts as EP4 antagonist has shown reduction in these stem cells and concomitant decrease in the tumor growth and the metastatic potentials to the lung. This effect was demonstrated in different murine mammary tumor cell lines including MMT 66.1, MMT 410.4, MMT 67, and MMT 410 as well as the human breast cancer cell lines MDA-MB-231, SKBR3, and MCF-7. Mammosphere formation was assessed after blocking EP4 and showed decreased stem cell frequency (P < 0.018). At high concentrations of Frondoside A, the size of the mammospheres was smaller but not the number in MDA-MB-231 cell lines.
| > Effect of Frondoside a on Potency of Other Chemotherapeutic Drugs|| |
In mice injected with this compound alone, cisplatin or combination of both using low concentration of Frondoside A (0.01 mg/kg/day) caused significant decrease in tumor weight and volume (P < 0.05). Frondoside A in this study showed to enhance the effect of cisplatin, and treated animals showed no side effects in term of behavioral and body weight changes posttreatment. The author did not elaborate on the behavioral test if any were used, and the monitoring of body weight presented in the data was only for 10 days, which might be considered of short duration. This mandates longer observation and more specific testing in order to make conclusions on Frondoside A side effects.
Another study on athymic mice injected with two types of human pancreatic cancer cell lines AsPC-1 and S2013 showed that the combination of the standard treatment (gemcitabine) with Frondoside A has statistically higher suppressive effect on cancer growth measured by tumor volume and tumor weight than each compound given alone. Activation of caspase-3 detected by immunohistochemical examination of the tumor developed in xenograft showed marked apoptosis in the treated groups compared to controls. Those treated with combination therapy showed significantly higher apoptosis rates. In this study, it was suggested that decrease tumor growth is mainly due to the activation of apoptosis pathways by both compounds. Frondoside A was also found to enhance the effect of paclitaxel in human breast cancer MDA-MB-231 xenograft. Treatment of MDA-MB-231 xenograft with intraperitoneal (ip) Frondoside A (100 μg/kg) daily for 24 days significantly decreased the tumor volume and weight (P < 0.001 and < 0.01, respectively). There was no toxicity recorded regarding changes in blood counts, creatinine level, and liver enzymes posttreatment. Furthermore, a study aimed at investigating the antigrowth effect of salinomycin on MDA-MB-231 cell lines demonstrated an enhanced effect of salinomycin when combined with 1.0 μM Frondoside A. Treatment of the urothelial carcinoma cell line (RT211) in vitro with a combination of Frondoside A and cisplatin or gemcitabine was associated with a synergistic enhancement of the cytotoxic effect of both drugs.
| > Effect of Frondoside a on Multi-Drug Resistant Cancer|| |
A major issue that is faced in the field of cancer therapy is the evolution of cancer cells to develop drug resistance. There are different mechanisms by which cancer cells become insensitive to the treatment; these include cancer cells altered metabolism of the drug, inactivation of the drug by the detoxification system in the body and overexpression of P-glycoprotein transporter., This is a transmembrane pump that causes efflux of substances from the intracellular space. Frondoside A extracted from a different sea cucumber strain (Cucumaria okhotensis) was found to inhibit this pump in multidrug-resistant (MDR) Ehrlich cancer cells. The cells were injected with a diffusible fluorescent probe attached to calcein. Resistant cancer cells will pump the calcein out of the cell and hence will have less intracellular fluorescence detection. Cells treated with subcytotoxic concentrations of Frondoside A (range 0.001–0.1 μg/ml) or its complex with cholesterol showed increased levels of fluorescence inside the treated cells indicating the inhibition of P-glycoprotein. This might suggest an additional function of Frondoside A as an option to use in MDR cancers.
One of the proposed mechanisms of drug resistance in cancer cells is that many of the drugs depend on functional p53 protein to exert their effect. The tumor suppressor gene; p53 is the most commonly mutated gene in human cancer ,,, and this might attribute to those cancers to be resistant and associated with poor prognosis. Frondoside A was shown to exert anticancer effect in different types of Burkitt's lymphoma cell lines including the multiresistant CA46 cells that have a mutated p53 gene. Being active in a p53-independent manner can be an additional mechanism by which Frondoside A overcomes multiple drug-resistant issues in cancer cells.
| > Suggested Mechanism of Action|| |
Frondoside A is thought to interact with the cell membrane leading to an increase in membrane permeability and hence, membrane lyzing. It was found that the sulfate group attached to C-4 of the xylose contributes to the enhanced Frondoside A activity , and compounds with high number of sulfate groups have lower lytic activity. Intracellular calcium concentration was also found to be enhanced by the number and position of the sulfate group, and it contributes to the variable functions of different extracts from sea cucumbers. A study comparing the efficacy of Frondoside A (monosulfate) to Frondoside B (bisulfate) and Frondoside C (no sulfate group) demonstrated the growth inhibitory effect of Frondoside A on the pancreatic cancer cell lines AsPC-1 and S2-013 to be greater than that of Frondoside B and C.
The structure of Frondoside A highly contributes to its functional efficacy as a pro-apoptotic and cytotoxic agent. Treatment with similar concentrations of Frondoside A decreased the leukemia cell line HL-60 viability after 24 h more than Frondoside A2-2 and Frondoside A4-2. Apoptosis measured by annexin V was detected in cells treated with 1 μM Frondoside A compared to 5 μM need for similar effect to be seen when treated with Frondoside A2-2 and Frondoside A4-2. This confirms the importance and the relation between the structure and the function of the compound.
A study aimed at investigating the pharmacokinetics of Frondoside A in pancreatic cancer compared the effect of Frondoside A to Frondoside B and Frondoside C. The mono-sulfated Frondoside A had a more potent inhibitory effect on cancer cell growth compared to the bi-sulfated Frondoside B. In this study, Frondoside C that lacks a sulfate group had no effect on cell growth. The isolated aglycon groups from these compounds also showed no effect. The study further investigated the effect of the rout of administration in in vivo models. Frondoside A given intraperitoneally decreased the tumor volume, but the oral rout lacks the effect. This emphasized the importance of the intact molecule for the function since the oral rout leads to the digestion of the glycoside chain attached and hence, the inactivation of the compound. The study also showed a longer bioavailability when given intravenously (iv) compared to ip.
A recently published study demonstrated the direct effect of Frondoside A on inhibiting p21 activated kinase 1 (PAK1) in A549 lung cancer cell lines. This highlights another mechanism by which Frondoside A exerts its anti-cancer effect. PAK1 is known to suppress the cyclin-dependent kinase inhibitor p21 and Frondoside A by inhibiting PAK1 removes this suppressive effect and up-regulates p21 in multiple cancer cell lines. Studies showed that inhibiting PAK1 decreases the phosphorylation of Akt and ERK/MAPK, induces apoptosis and decreases the expression of leukemia stem cell markers. Frondoside A treatment decreases the phosphorylation and the activation of the pro-survival pathways; p38/MAPK and ERK1/2. PAK1 exerts its effect by promoting the nuclear translocation of the transcription factor, signal transducer and activator of trascription (STAT) which up-regulated multiple genes involved in leukemogenesis such as the anti-apoptosis gene Bcl-xL., PAK1 also leads to the phosphorylation and inhibition of the pro-apoptosis protein Bad, hence, the inhibition of apoptosis. Frondoside A, being a direct inhibitor of PAK1, might have its different anti-cancer effects through this mechanism.
Frondoside A showed induction of apoptosis in caspase-independent manner in some cancer cell lines. A study that investigated the possible mechanism in Burkitt lymphoma showed that treatment with Frondoside A was associated with the release of proteins from the mitochondria such as AIF, which was released into the cytoplasm, cleaved into the active form, and translocated into the cell nucleus. AIF translocation to the nucleus can lead to chromatin condensation and cell death by apoptosis.
| > Conclusion|| |
Marine plants and animals are rich sources of bioactive compounds with different structures contributing to the variability of function. The sea cucumber; C. frondosa is an invertebrate that has been used as food supplement since long time. Its extracts have shown immune, anti-inflammatory, and anticancer properties.
Frondoside A, is a triterpenoid mono-sulfated glycoside from C. frondosa that has drawn the attention of the researchers for its marked anticancer effects. As an anti-proliferative agent, it inhibits cancer growth in cell lines as well as animal cancer models including pancreas, breast, lung, colon and prostate cancers. It induces cancer cell death mainly by apoptosis. Most studies have approved its induction of apoptosis though the activation of the caspases and the mitochondrial pathway (intrinsic pathway) except for few studies that suggested alternative pathways to be involved which are caspase independent; this has to be further investigated. Other anticancer properties of the compound include inhibition of cancer invasion, metastasis and angiogenesis.
Its effect on suppressing cancer stem cell though EP4 receptor is yet to be fully explored in breast cancer as well as other types of hormonal dependent cancers. In addition to its anticancer function, Frondoside A can retain chemoresponsiveness in MDR cancers. With currently available chemotherapeutic drugs, long-term cure from cancer is compromised by the treatment side effects. Frondoside A, being a natural substance, has no reported side effects, which makes it safer. Its anticancer effect is not tissue specific, and this makes it a potential treatment for many types of malignant diseases and an attractive future cancer therapy. Studies are also required to optimize the compound's concentrations in animal testing as a preliminary step before testing in humans. More studies are needed to fully explore its mechanism of action and the different pathways it interacts with.
Frondoside A being inactive through the oral rout makes its use in in vivo experiments difficult. Methods to overcome this difficulty should be explored if the compound is to reach clinical trials. Its administration through the (ip) rout is invasive and might be associated with procedure risks. By the (iv) rout, the bioavailability is long and dose optimization is needed. Further studies are required to investigate the exact mechanism of the compound's absorption and elimination in the body.
The author would like to thank Prof. Thomas E. Adrian for providing an original figure of Frondoside A.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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