Al Shemaili J et al. (2016), Pharmacokinetics in Mouse and Comparative Effec...

ECB-ART-44766

Mar Drugs 2016 Jun 17;146:. doi: 10.3390/md14060115.

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Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer.

Al Shemaili J , Parekh KA , Newman RA , Hellman B , Woodward C , Adem A , Collin P , Adrian TE .

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The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of ~1 µM. Frondoside B was less potent (EC50 ~2.5 µM). Frondoside C and the aglycone had no effect. At 100 µg/kg, frondoside A administered to CD₂F₁ mice as an i.v. bolus, the Cpmax was 129 nM, Cltb was 6.35 mL/min/m², and half-life was 510 min. With i.p. administration the Cpmax was 18.3 nM, Cltb was 127 mL/min/m² and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 µg/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.

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Genes referenced: LOC100887844 LOC574780 LOC590751

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	Figure 1. Effects of frondoside A, B and C on viability of AsPC-1 and S2013 human pancreatic cancer cells after 24 h of incubation. *** p < 0.001.
	Figure 2. Effects of frondoside A, B and C and their aglycone on viability of AsPC-1 and S2013 human pancreatic cancer cells after 48 h of incubation. *** p < 0.001.
	Figure 3. Effects of frondoside A administered either orally or intraperitoneally at a dose of 100 µg/kg/day on growth of AsPC-1 human pancreatic cancer xenografts in athymic mice over a 30-day period.
	Figure 4. Plasma concentration of frondoside A versus time plot following administration of frondoside A at a dose of 100 µg/kg intravenously or intraperitoneally in CD2F1 mice. Each point represents the mean and SD of plasma concentration in five animals.
	Figure 5. Structures of frondosides A, B, C (mono, di and tri-sulphated frondoside).