Cellular and Molecular Growth Regulation

The major focus of the Section of Cellular and Molecular Growth Regulation is directed at identification and characterization of novel plant compounds that regulate the growth of tumor cells and endothelial cells. The major emphasis during the past 24 months has been on the biochemical and biological characterization of a triterpene glycoside with an unusual ester linkage obtained from a desert legume plant from Australia. This compound, or mixture of compounds, induces cytotoxicity against a wide range of hematopoietic and solid tumor cell lines as well as freshly isolated ovarian cancer cells. The triterpene compound induces apoptosis in the Jurkat leukemia cell line. It is minimally cytotoxic in vitro against nontransformed cells. In vivo, the compound is extremely active in two chemopreventive models: the initiation and promotion phases of the murine dimethylbenzanthracene (DMBA) mouse skin carcinogenesis model as well as the rat aberrant colonic crypt assay. The mechanism of action is being investigated and focuses on the inhibition of the PI-3K pathway.

This compound also has potent in vitro and in vivo anti-inflammatory effects and appears to inhibit activation of NF-kappaB.

Terpenoids are natural constituents of plants and of invertebrate and vertebrate animals. They play key roles in defense signaling by plants against predators such as insects. The triterpenoids are often pentacyclic compounds, usually containing complex side chains. The sugars may not be required for in vitro antitumor activity, but their presence may be important for water solubility and in vivo activity.

Present and future work includes complete purification and structural characterization of the triterpene glycoside, metabolic labeling studies, continued work on mechanism of action (including effects on endothelial cells, angiogenesis and cholesterol metabolism) and genetic studies of sensitive and resistant cells by RNA analysis on microarrays and DNA chips. Studies of the biological effects of this terpenoid on model organisms are being pursued. Based on the structure and known biology of other terpenoids in human biology, the triterpenes may act as hormonal substances and therefore may bind to a known or orphan nuclear receptor.

The premise of our section is that plants have evolved to manufacture a wide variety of secondary metabolites that act as deterrents for dangerous predators. Many of the target pathways of these plant metabolites have been preserved in evolution from yeast to Drosophila to man and may be important constituents of the malignant phenotype. Discovery of plant metabolites that interrupt critical pathways in a cancer cell should yield exacting new leads for drug discovery.

Thus, we are continuing to study extracts of other arid land plants in the hope of discovering novel compounds with unique mechanisms of action against malignant cells or endothelial cells. This project is part of a collaboration with the University of Arizona (chemistry) and Boyce Thompson Plant Institute at Cornell University (plant biology).