Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer

Abstract

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.

Marine natural products

“…737 The sea cucumber triterpenoid glycoside frondoside A 738 exhibits activity in a human pancreatic mouse xenogra model but only when given intraperitoneally (oral gavage delivery had no effect). 739 It also exhibits activity towards prostate cancer cell lines in vitro and in vivo. 740 A related sea cucumber triterpenoid glycoside, echinoside A, 741 exhibited diurnal time-dependent inhibition of fatty acid biosynthesis in mice while enhancing mitochondrial fatty acid b-oxidation.…”

The Anti-Cancer Effects of Frondoside A

“…The effects of frondoside A on cell viability or proliferation has been tested using multiple different methods in many different cancers. This has included studies on pancreatic ductal adenocarcinoma, breast, non-small cell lung, colon, prostate, cervix, bladder (transitional cell), Burkitt lymphoma, malignant germ cell, and acute leukemias [ 11 , 12 , 13 , 14 , 16 , 18 , 19 , 20 , 21 , 23 , 24 , 25 , 26 , 27 ]. Methods employed have included cell counts, thymidine incorporation, MTT assay, and CellTiterGlo (Promega, Madison, WI, USA) assays.…”

“…As mentioned above, several other sea cucumber-derived glycosylated triterpenoids have anti-cancer effects [ 5 , 6 , 7 , 8 , 9 , 10 ]. The activity of frondoside A was compared with frondosides B and C. In AsPC-1 and S2103 human pancreatic cancer cells studied in culture, frondoside A more potently reduced the number of viable cells than its disulphated cousin, frondoside B [ 26 ]. The trisulphated frondoside C and the parent aglycone had no effect on cell viability [ 26 ].…”

“…The pharmacokinetics of frondoside A were investigated in mice following intravenous (IV) and intraperitoneal (IP) administration at a bolus dose of 100 µg/kg. Plasma frondoside A concentrations were measured using a liquid chromatography mass spectrometry (LC-MS/MS) method [ 26 ]. The mean C max following IV administration of frondoside A was 129nM, while that following IP administration was 18.3 nM at 45 min, which is about seven-fold lower than with IV administration at the same dose [ 26 ].…”

“…Here, we will review the nature of frondoside A, its effects on cancer cell growth, cell cycle, apoptosis, angiogenesis, migration, invasion, and formation of metastases [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. We will also review the pharmacokinetics, toxicity, interactions with other anti-cancer therapeutics, effects on the immune system, and possible mechanisms of action of this compound [ 13 , 16 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].…”