Intracellular signaling pathways that mediate the effects of growth
factors and oncogenes in cancer cells.
1) Cancer drugs active against growth factor and oncogene
signalling
Nearly all cancer drugs developed in the past have been found
to be active against DNA or DNA synthesis in the nucleus of the
cell. My laboratory has adopted a novel approach to cancer
drug development by targeting, instead of DNA, the mechanisms
that control DNA synthesis and gene function. Cells respond
to their environment and to the stimulus for proliferation provided
by growth factors through receptors located on the cell surface.
They then transfer the message to the nucleus to activate the
expression of specific genes. This transfer of information
occurs through a series of intracellular signalling pathways.
These pathways are where oncogenes (cancer genes) are thought
to produce their effects by causing the cells to receive a constitutive
signal to grow. If these oncogene-activated signalling
pathways can be inhibited it might be possible to selectively
inhibit the growth of cancer cells. The major focus of our
work is to examine the mechanisms of oncogene and growth factor
signalling and to develop new drugs to inhibit the signalling
pathways. The drugs come from extracts of plants collected
from the U.S.A., Chinese traditional medicinal plants, and Indonesia.
We are also studying new drugs that act as antimetabolites of
myo-inositol, a natural sugar that is an essential component of
the signalling pathways. My lab coordinates the activity
of several other research groups around the country and the far
East and works with the Eli Lilly drug company and the National
Cancer Institute as part of a National Cooperative Natural Products
Drug Discovery Grant to develop novel anticancer drugs.
2) Cancer Drugs and flavoenzymes
Some of the most active anticancer drugs currently available have
as part of their structure the quinone group. We have found
that these quinone anticancer drugs are metabolized by certain
key flavoenzymes to give reactive products that inhibit the enzymes.
The quinones are, thus, acting as so called "suicide-substrates".
The inhibition of these flavoenzymes can, in turn, lead to the
inhibition of certain pathways necessary for DNA synthesis and
cell growth. This could be how the anticancer quinone drugs
produce some of their effects. With this knowledge we are
in a position to develop more active anticancer drugs that act
in this novel way. One of the flavoenzymes inhibited in
this way is thioredoxin reductase which controls the redox state
of the protein thioredoxin. Thioredoxin is a key regulatory
peptide involved in signalling mechanisms for growth factors and
oncogenes, it controls the activity of several enzymes, transcription
factors, and itself may be a growth factor. Our work is
now focussing on the role of thioredoxin reductase and thioredoxin
in controlling normal and cancer cell function.
Berggren M, Powis G: Alternative splicing is associated with
decreased expression of the redox proto-oncogene thioredoxin-
1 in human cancers. Arch. of Biochem. & Biophy. 389:1-6, (2001).
Berggren,M., Husbeck,B., Samulitis,B., Baker,A., Gallegos, A.
and Powis, G. Thioredoxin Peroxidase-1(peroxiredoxin-1) Is Increased
in Thioredoxin-1 Transfected Cells and Results in Enhanced Protection
Against Apoptosis Caused by Hydrogen Peroxide but Not by Other
Agents Including Dexamethasone, Etoposide, and Doxorubicin. Arch
of Biochem & Biophy, 103-109, (2001).
Rong, SB., Hu, Y., Enyedy, I., Powis, G., Meuillet, EJ., Wu,
X., Wang, R., Wang, S., and Kozikowski, A.: Molecular Modeling
Studies of the Akt PH domain and its interaaction with Phosphoinositides.J.Med
Chem,44,898-908, (2001)
Wipf, P., Hopkins, TD., Jung, JK., Rodriguez, S., Birmingham,
A., Southwick, EC., Lazo, J., and Powis, G.: New Inhibitors of
the Thioredoxin-thiordoxin reductase system bassed on a naphoquinone
spiroketal natural product lead., Bioorganic & Med Chem Letters
11, 2637-2641, (2001).
Powis, G., Meuillet, E.,Berggren, M., Williams, R., & Coon,
A. The tumor suppressor PTEN is inhibited by binding of thioredoxin-1
in a REDOX dependent manner. Proceedings of the American Assoc.
for Cancer Res. 42: 418, (2001).
Kakolyris, S., Giatromanolaki, A., Koukourakis, M., Powis, G.,
Souglakos, J., Efthimios, S., Georgoulias, V., Gatter, KC., &
Harris, AL. Thioredoxin expression is associated with lymph node
status and prognosis in early operable non-small cell lung cancer.
Clin. Cancer Res. 7: 3087-3091, (2001).
