Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer.
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.
Department of Physiology, Faculty of Medicine, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE. 201617836@uaeu.ac.ae.
Jasem
J
Al Shemaili
Department of Physiology, Faculty of Medicine, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE. kparekh@uaeu.ac.ae.
Khatija A
KA
Parekh
Phoenix Biotechnology Inc., San Antonio, TX 78217, USA. rnewman@phoenixbiotechnology.com.
Robert A
RA
Newman
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 75105, Sweden. Bjorn.Hellman@farmbio.uu.se.
Björn
B
Hellman
Coastside Bio Resources, Deer Isle, ME 04627, USA. carlw@coastsidebio.com.
Carl
C
Woodward
Department of Pharmacology, Faculty of Medicine, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE. abdu.adem@uaeu.ac.ae.
Abdu
A
Adem
Coastside Bio Resources, Deer Isle, ME 04627, USA. petercollin@coastsidebio.com.
Peter
P
Collin
Department of Physiology, Faculty of Medicine, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE. tadrian@uaeu.ac.ae.
Thomas E
TE
Adrian
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006027:Glycosides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012616:Sea Cucumbers / Q000737:chemistry; D014315:Triterpenes / Q000493:pharmacokinetics* / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D006027:Glycosides; D014315:Triterpenes; C524890:frondosin A
cancer; frondoside A; pancreatic cancer; pharmacokinetics