Jordan U. Gutterman, M.D.
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 2 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).
- Choubey D, Gutterman JU. Inhibition of E2F-4/DP-1-stimulated
transcription by p202. Oncogene 15:291-301, 1997
- Choubey D, Li S-J, Gutterman JU, Datta B, Lengyel
P. Inhibition of E2F-mediated transcription by p202. EMBO
J 15:5668-5678, 1996
- Gutterman JU. Clinical investigators: The driving
force behind drug discovery. Nat Biotechnol 15:598-599, 1997
- Kudelka AP, Levy T, Verschraegen CL, Edwards CL, Piamsomboon
S, Termrungruanglert W, Freedman RS, Kaplan AL, Kieback DG,
Meyers CA, Jaeckle KA, Loyer E, Steger M, Mante R, Mavligit
G, Killian A, Tang RA, Gutterman JU, Kavanagh JJ. A
phase I study of TNP-470 administered to patients with advanced
squamous cell cancer of the cervix. Clin Cancer Res 3:1501-1505,
- Mujoo K, Maneval DC, Anderson SC, Gutterman JU. Adenoviral-mediated
p53 tumor suppressor gene therapy of human ovarian carcinoma.
Oncogene 12:1617-1623, 1996