Sea Cucumber Derived Triterpenoid Glycoside Frondoside A: A Potential Anti-Bladder Cancer Drug

Abstract

Bladder cancer is a highly recurrent disease and a common cause of cancer-related deaths worldwide. Despite recent developments in diagnosis and therapy, the clinical outcome of bladder cancer remains poor; therefore, novel anti-bladder cancer drugs are urgently needed. Natural bioactive substances extracted from marine organisms such as sea cucumbers, scallops, and sea urchins are believed to have anti-cancer activity with high effectiveness and less toxicity. Frondoside A is a triterpenoid glycoside isolated from sea cucumber, Cucumaria frondosa. It has been demonstrated that Frondoside A exhibits anti-proliferative, anti-invasive, anti-angiogenic, anti-cancer, and potent immunomodulatory effects. In addition, CpG oligodeoxynucleotide (CpG-ODN) has also been shown to have potent anti-cancer effects in various tumors models, such as liver cancer, breast cancer, and bladder cancer. However, very few studies have investigated the effectiveness of Frondoside A against bladder cancer alone or in combination with CpG-ODN. In this study, we first investigated the individual effects of both Frondoside A and CpG-ODN and subsequently studied their combined effects on human bladder cancer cell viability, migration, apoptosis, and cell cycle in vitro, and on tumor growth in nude mice using human bladder cancer cell line UM-UC-3. To interrogate possible synergistic effects, combinations of different concentrations of the two drugs were used. Our data showed that Frondoside A decreased the viability of bladder cancer cells UM-UC-3 in a concentration-dependent manner, and its inhibitory effect on cell viability (2.5 μM) was superior to EPI (10 μM). We also showed that Frondoside A inhibited UM-UC-3 cell migration, affected the distribution of cell cycle and induced cell apoptosis in concentration-dependent manners, which effectively increased the sub-G1 (apoptotic) cell fraction. In addition, we also demonstrated that immunomodulator CpG-ODN could synergistically potentiate the inhibitory effects of Frondoside A on the proliferation and migration of human bladder cancer cell line UM-UC-3. In in vivo experiments, Frondoside A (800 μg/kg/day i.p. for 14 days) alone and in combination with CpG-ODN (1 mg/kg/dose i.p.) significantly decreased the growth of UM-UC-3 tumor xenografts, without any significant toxic side-effects; however, the chemotherapeutic agent EPI caused weight loss in nude mice. Taken together, these findings indicated that Frondoside A in combination with CpG-ODN is a promising therapeutic strategy for bladder cancer.

Advancements and challenges in pharmacokinetic and pharmacodynamic research on the traditional Chinese medicine saponins: a comprehensive review

“…Frondoside A, a sulfated saponin from sea cucumbers, inhibits the PAK1-dependent growth of lung and pancreatic cancer cells ( Nguyen et al, 2017 ). Other saponins found in sea cucumbers, such as holotoxin A1 and holothurin A, display anticancer activity, making them valuable for functional food and nutraceutical applications ( Song et al, 2017 ; Ru et al, 2023 ). A new sulfated saponin from sea cucumber exhibits antiangiogenic and antitumor activities both in vitro and in vivo ( Hossain et al, 2020 ).…”

Saponins of North Atlantic Sea Cucumber: Chemistry, Health Benefits, and Future Prospectives

“…It was demonstrated in the reports of Sajwani [ 15 ] and Al Shemaili and Parekh [ 69 ] that frondoside A has a greater growth inhibitory effect on the pancreatic cancer cell lines AsPC-1 and S2-013 compared with frondoside B and C. Studies have also reported the higher antiangiogenic and antimetastatic effects on the cancer inhibitory effect using tumor-bearing mice than other types of frondosides [ 62 , 63 , 64 ]. Recently, Ru and Chen [ 70 ] investigated the individual anti-bladder cancer effects of both frondoside A and its combination with CpG oligodeoxynucleotide (CpG-ODN) in vitro and in vivo. From the results of the study, it was revealed that frondoside A has a potential anti-bladder cancer activity by inhibiting cell viability and migration, inducing apoptosis, and affecting the cell cycle.…”

Triterpene Glycosides from Cucumaria frondosa, a North Atlantic Mass Harvesting Sea Cucumber: A Comprehensive Structures and Biological Activities Review

“…The authors concluded that the blocking of P-glycoprotein activity resulted in decrease of multidrug resistance, and the glycoside and its complex with cholesterol may be potential inhibitors of multidrug resistance in tumor cells. Ru et al (2023) [45] have demonstrated the efficacy of frondoside A (6) against bladder cancer. They have found anti-proliferative, anti-invasive, anti-angiogenic, and potent immunomodulatory effects.…”