EXECUTIVE SUMMARY

Induction of Apoptosis by Novel Diterpenes

from the Soft Coral Xenia Elongata

SUMMARY:  Researchers at the Center for Marine Biotechnology, led by Drs. Paul Falkowski and Richard Lutz at Rutgers University have isolated four new diterpenes from the soft coral Xenia elongata.  The molecular structures of all four compounds were determined by NMR spectroscopy in combination with mass spectral data analysis.  The diterpenes were found to induce apoptosis in an apoptosis induction assay using genetically engineered cell lines at nanomolar concentrations.  Transcriptional profiling with human breast cell lines reveals the pathway for inducing cell death is unique.  Siuta Consulting has been retained by Rutgers to identify partners for these compounds.

BACKGROUND:  Screening of organic extracts of marine algae and cyanobacteria for mechanism-based anticancer agents has led to the discovery of new chemotypes showing antiproliferative properties.  Several of these natural products are in late stage clinical trials. Cytotoxic chemotherapeutics currently in use rely on the ability to selectively target proliferating cells, which are enriched in tumors.  Unfortunately, these drugs are also cytotoxic to proliferating normal cells, accounting for the severe and potentially lethal side effects that limit dosing and effectiveness.  Moreover, while sometimes effective, cytotoxic chemotherapy non-specifically damages both normal and tumor cells, with successful treatment often relying on preferential induction of cell death by apoptosis in tumor cells.  Tumor cells, however, evolve apoptosis-resistance mechanisms that confound treatment necessitating the development of the therapeutic means for restoring the capacity for apoptosis in cancers.  While many conventional cytotoxic chemotherapeutics trigger apoptosis indirectly by inflicting cellular damage, recent efforts have evolved to develop agents that specifically target or activate the apoptotic pathway.

TECHNOLOGY:  Soft corals belonging to the genus Xenia are a rich source of diterpenoids which have been found to have interesting biological activities, specifically cytotoxicity against several human cancer cell lines.  In an effort to discover and develop new marine natural product biomedicinals, the researchers in the Center for Marine Biotechnology have screened scores of organic extracts from several marine organisms and found that the organic extract of the soft coral, Xenia elongata, possessed unusually promising apoptosis induction activity.  Four novel diterpenes were isolated, purified and their structures fully characterized.  Three of the four compounds were found to be able to induce apoptosis in an apoptosis induction assay at therapeutic concentrations.  These molecules are being synthesized for further mechanistic studies.

PATENT STATUS:  A provisional patent application claiming these novel diterpenes was filed on March 5, 2007.

PUBLICATIONS:  E H. Andrianasolo, L. Haramaty, K. Degenhardt, R. Mathew, E. White, R. Lutz, and P. Falkowski, Induction of Apoptosis by Diterpenes from the Soft Coral Xenia elongata, J. Nat. Prod., 70 (10), 1551-1557 (2007)