Frondanol^® A5: A novel nutrapreventive and therapeutic agent derived from sea cucumber showing promising antiproliferative, antiinflammatory and antiangiogenic activities.

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We continue to explore extracts and pure molecules derived from the holothurian (sea cucumber) Cucumaria frondosa. With support from the NCI's RAPID Program, we investigated Frondanol® A5, for indications of therapeutic and preventive effects against cancer. We have shown that Frondanol A5 and its glycoside components inhibit growth of pancreatic cancer cells through induction of apoptosis. Research indicated that Frondanol® A5 mediated cell death was associated with an increase in p-21^Cip1, phosphorylation of p38 kinase, and triggered the apoptotic caspase cascade. Isolated crude glycosides from Frondanol A5 were found to inhibit COX-1 and COX-2 in a conc.-dependent manner, while the non-saponifiable fraction from Frondanol® A5 exhibited strong inhibition of the 5-lipoxygenase pathway. We have also previously shown that glycosides of Frondanol® A5 appear to block the G-coupled prostaglandin EP-1 receptor and show an inhibitory activity in an arachidonic acid-induced mouse ear inflammation model. We now show that in a DMBA Mouse Mammary Organ Culture assay, Frondanol A5 inhibits development of breast cancer ductal lesions by 75% using very low drug conc. In the B[a]P-induced Rat Tracheal Epithelial foci inhibition assay, Frondanol® A5 significantly inhibited (86.4% decrease) transformation at 0.3 ug/ml. A 98% pure glycoside component of Frondanol® A5, designated Frondoside A, inhibited microtubule formation by 88% (at 1 uM) in a HUVEC based angiogenesis assay. Pure Frondoside A has also been shown to have immunomodulatory effects. Frondoside A, was injected subcutaneously to Staph. aureus infected mice. Saline controls showed 10% survival, while Frondoside A treated mice showed 40% survival which was considered to be a significant survival improvement in this difficult test. Finally, microarray analyses of the effect of Frondoside A in the pancreatic cancer cell line S2-013 has shown increased expression of anti-oxidant genes associated with modulation of free radical damage (SOD and AKR1C1) and down-regulation of several pro-inflammatory genes and genes involved in cyclin dependent kinase pathways. Our data thus indicate the multi-mechanistic potential of Frondanol® A5 and its subcomponent glycoside Frondoside A as potentially useful novel chemopreventive agents. As a popular Oriental delicacy for more than 1,000 years, we suggest that sea cucumber glycosidic compounds are a safe cancer nutrapreventive food supplement with pronounced beneficial effects in biochemical and genomic pathways now known to contribute to cancer initiation, progression and metastatic pathology. This has been supported by the National Cancer Institute, Division of Chemoprevention RAPID Program, American Institute for Cancer Research, Maine Technology Institute and the Russian Academy of Science in Vladivostok, Russia.