The broad goal of the proposed research is to explore selected shallow and deep water sponges for their synthesis of bioactive natural products with potential chemotherapeutic uses in the treatment of cancer, especially lung cancer. Protein kinase C (PKC) has been selected as the mechanistic focus in the proposed research based on 1) the concept that carcinogens can be viewed as a distortion in signal transduction, 2) the belief that effective new anticancer treatments can be obtained through research on new targets other than the traditional ones of the cell nucleus and DNA, and 3) the pivotal role recognized for PKC in processes mediating cell proliferation and differentiation. A number of naturally derived substances have recently been discovered to affect PKC and exhibit cytotoxic or antitumor properties, i.e., the bryostatins, which were derived from the marine bryozoan, Bugula neritina, and are scheduled for phase I clinical trials, staurosporine, sangivamycin and calphostin. Shallow water marine sponges have proven to be chemically rich, however, their metabolites have been poorly studied with respect to their effects on signal transduction. Recent research on deep water marine sponges has revealed that this understudied group is also a rich source of novel, bioactive compounds with potential utility as chemotherapeutic agents. During the three-year period of the proposed research, the emphasis will be placed on the discovery of marine sponge-derived natural products that: -have demonstrable activity against human lung cancer cells (A549) in vitro and in vivo, and -exhibit significant agonistic or antagonistic activity against PKC.
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| Longley, R E; McConnell, O J; Essich, E et al. (1993) Evaluation of marine sponge metabolites for cytotoxicity and signal transduction activity. J Nat Prod 56:915-20 |
