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Education, Training, and Awards
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Education:
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Baccalaureate: Wayne State
University, B.S., Biological Sciences |
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Graduate:
Wayne State University,
M.S., Biophysics, Biological Science |
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Graduate: Wayne State
University School of Medicine, Ph.D., Molecular Endocrinology |
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Training:
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Post-doctoral:
Wayne State University School of Medicine, Department of
Biochemistry and Molecular Biology |
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Appointments and Awards:
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Assistant Professor of Physiology, Wayne State University School
of Medicine |
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Associate Member, Institute of Environmental Health Sciences (IEHS),
Center for Molecular and Cellular Toxicology, Gene Regulation and
Genetics Program, Wayne State University |
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Awarded:
Thomas C. Rumble University Fellowship |
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Awarded: National Research Service Award, National Cancer
Institute |
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Awarded: Virtual Discovery Grant, Karmanos Cancer Institute |
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Focus of Research
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- The impact of diet on cancer
- An in vitro cell line model
was developed in our laboratory to study the consequences of
prolonged dietary agent exposure on tumor cell growth and
responses to chemotherapy.
We have recently developed a series of paired cell lines to
study the effects of diet on cancer progression and drug
treatment responses. The cell lines in this model consist of
parent and subline cell pairs that derive from a single
genetically identical cell line of origin. The sublines were
established by long term exposure to very low doses of dietary
agents or pharmaceuticals. The corresponding parent cell lines
were initiated and maintained in parallel cultures using
unsupplemented, but otherwise identical media.
By taking this approach we have shown that the continuous
exposure of tumor cells to commonly used dietary agents, like
the polyphenols in green tea, the phytoalexins in red wine, or
the isoflavones in soy, leads to changes in cell phenotype.
More specifically, we observed changes in the morphology (Figure 1), growth rates, serum dependence, karyotype
(Figure 2), motility, and drug treatment responses of the sublines but
not the corresponding parent cell lines, which had been
maintained, propagated, and tested in parallel. Remarkably,
the novel characteristics acquired by the subline cells were
found to be stable and heritable, as they persisted in
subsequent subline cell generations long after removal of the
dietary agent from the media. Nevertheless, certain features
typical of the originating cell lines were also retained by
the subline cells. For example, the characteristically high
estrogen receptor alpha expression levels present in the human
MCF7 breast cancer cell line of origin was repeatedly detected
in both (parent and subline cell) derivatives (Figure 3).
Significant among the changes identified in the subline cells
was the acquisition of hypersensitive responses to the widely
used chemotherapeutic drug, Taxol™. Striking increases in the
cytotoxic sensitivity of Taxol-treated sublines but not in the
identically-treated parents, were revealed in experiments used
to test cell viability (Figure 4), morphology (Figure 5), clonogenic survival, and cell cycle distribution (Figure 6).
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Figure 4. Differential Cytotoxic |
Figure 5. Morphologic Responses to Taxol |
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Differential Cytotoxicity.
The cytotoxic effects induced by exposure to Taxol for 24
hours are shown in Fig. 4,
and are calculated as the percentage of cell death per day
for each of the subline-parental cell pairs shown. |
Morphologic Responses to Taxol.
Photomicrographs showing the morphologic responses of
parental and subline cell pairs are provided
in Fig. 5. The images
shown were taken before and 24 hrs after exposure to
vehicle (a-b, e-f) or Taxol (c-d: 3 nM; g-h: 10 nM) during
exponential growth, for the cell lines indicated.
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Members of the Lab
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 Karl Kado,
Andrew Forsyth, and Priyesh Patel (shown
here from left to right) have began working as a team on the
role played by curcumin in cancer.
Curcumin, a phytochemical and potential chemopreventive, was
originally isolated from the spice known as ‘turmeric’ - used in
curries, as a food additive, and as a coloring(1-2).
Studies have shown that even when consumed on a regular basis,
curcumin only reaches subnanomolar levels in circulation.
Led by Priyesh, this group of students set out to perform
experiments that would allow them to mimic this ‘physiologic’
concentration and then test it in a basic science laboratory
setting.
Starting with a well-known human prostate cancer cell line, DU145,
they began to subculture cell line derivatives in growth media that
had been supplemented with low, dietary-like concentrations of
curcumin, similar to what would be found in the human circulation.
They continued this regimen, without interruption, for a consecutive
six month period.
The subline that emerged from this unique propagation regimen, which
they called the ‘DU-CU’ cell line, was subsequently characterized
and tested.
The first goal undertook by these students was to evaluate the
phenotypic characteristics of this newly established subline for any
changes that would imply alterations in its neoplasticity.
Neoplastic changes were judged by evaluating the parameters of
growth, clonogenicity, morphology, and motility in the DU-CU subline
cells (that had been generated by chronic exposure to low doses of
curcumin) relative to the original curcumin-naïve, DU145 parent cell
line using side-by-side assays that were conducted in parallel.
Using this experimental
approach, a number of changes were indeed detected, and will be
described in a manuscript that is currently in preparation (3).
These students, who were juniors and seniors at the time they did
these studies, have since become first year medical students at
Wayne State University. Some of them will apply for support during
the summer so that they can perform chemosensitivity testing studies
using the curcumin-exposed subline cells that they have already
generated and begun characterizing.
Findings from these and other similar studies may ultimately be used
to advise cancer patients of the dietary approaches that would be
most appropriate.
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1.
Agarawal, B.B., et al Curcumin: The Indian Solid Gold. Adv
Med Exp Biol 595: 1-75, 2007.
2.
Agarawal, B. B., et al Anticancer Potential of Curcumin:
Clinical and Preclinical Studies. Anticancer Res 23(1A):363-398,
2003.
3.
Patel, P., Kado, K., Forsyth, A., Schwartz, J. Chronic Curcumin
Exposure of Tumor Cells in Culture. In Preparation, 2007.
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We have four new students (shown from left to right): Janjenali Villaflor or ‘JJ’,
Jeff Kangas, Faryal Osman, and Amrita Vempati.
JJ, Jeff, and
Amrita are undergraduates in the Honors Program at Wayne
State University and Faryal is a Masters student who is
currently in the Basic Medical Sciences progam at the School
of Medicine. All four of these students are on a mission to
investigate the link between diet and cancer.
The students
were first trained in mammalian cell culture, sterile
laboratory practices, and basic molecular biology and have
since begun to use
their training to
address two major questions surrounding the use of
phytochemicals in patients with cancer.
Namely, how could the consumption of a phytochemical
that is repeatedly obtained from the diet in very low doses:
a)
influence the growth of a pre-existing tumor; and/or,
b)
change the way that that tumor responds to chemotherapy.
The phytochemicals that these
students have chosen to evaluate are: caffeic acid, a
phenolic acid that occurs naturally in coffee beans and
other agricultural products; curcumin, which was originally
isolated from the spice known as ‘tumeric’; and, resveratrol,
found in the skins of red grapes, red wine, and several
other food products.
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Selected
Publications
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Schwartz, J.A.
and Mizukami, H. A Metal-Linked Gapped Zipper Model Is Proposed
for the
90kda Heat Shock Protein - Estrogen Receptor Interface.
Med. Hyp. 35:140-145, 1991 |
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Schwartz, J.A.,
Mizukami, H. and Skafar, D.F. A Metal-Linked Gapped Zipper Model
is Proposed
for the Hsp90-Glucocorticoid Receptor Interaction. FEBS Letts. 315: 109-113, 1993 |
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Schwartz, J.A.
and Skafar, D.F. Ligand Mediated Modulation of Estrogen
Receptor Conformation by Estradiol Analogs. Biochem.
32:10109-10115, 1993 |
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Schwartz, J.A.
and Skafar, D.F. A-Ring Nitro- And Amino-Substituted
Estradiol Analogs Produce a Negative Cooperative or
Non-Cooperative [3H]estradiol-Estrogen
Receptor Binding Mechanism. Biochem.33:13267-13272, 1994 |
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Schwartz, J.A.
and Brooks, S.C. Neutral Mutations to Three Acidic AF2
Residues in the Mouse Estrogen Receptor Confer Agonist
Activity to A-Ring Isomers of Estradiol. J. Steroid Biochem.
Mol. Biol., 62: 173-184, 1997 |
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Schwartz, J.A.
and Brooks, S.C. Changes In The Structure of the Ligand or
Substitutions to AF2 Residues in the Estrogen Receptor Make
Independent Contributions to Coactivator Sensitivity by SRC-1.
J. Steroid Biochem. Mol. Biol. 67: 223-232, 1998 |
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Schwartz, J.A.,
Lui, G., and Brooks, S.C.
Genistein-Mediated Attenuation of Tamoxifen Induced Antagonism
from Estrogen Receptor Regulated Genes. Biochem.
Biophys. Res. Comm. 253: 38-43, 1998 |
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Lui, G., Schwartz, J.A.,
and Brooks, S.C.
p53 Down Regulates ER Responsive Genes by Interfering with the
Binding of ER to ERE. Biochem. Biophys. Res. Comm
264:359-364, 1999
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Lui, G., Schwartz, J.A., and Brooks, S.C.
Estrogen Receptor Protects p53 from being Degraded by hdm2.
Cancer Research 60: 1810-1814, 2000
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Schwartz, J.A.,
Zhong, L., Deighton-Collins, S., Zhao, C., and Skafar, D.F.
Mutations Targeted to a Predicted Helix in the Extreme Carboxy-Terminal
Region of the Human Estrogen Receptor-Alpha Alter its Response to
Estradiol and 4-Hydroxytamoxifen. J. Biol. Chem. 277:
13202-13209, 2002 |
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Atanaskova, N., Keshamouni, V.G., Krueger, J.S.,
Schwartz, J.A., Miller, F., and Reddy, K.B.
MAP Kinase/Estrogen Receptor Cross-Talk Enhances
Estrogen-Mediated Signaling And Tumor Growth but does not
Confer Tamoxifen Resistance. Oncogene 21: 4000-4008,
2002 |
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Zhao C, Koide A, Abrams J, Deighton-Collins S, Martinez A,
Schwartz JA,
Koide S, and Skafar DF.
Mutation of Leu-536 in human Estrogen Receptor-α Alters the
Coupling between Ligand Binding, Transcription Activation, and
Receptor Conformation. J. Biol. Chem.
278:27278-27286, 2003. |
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Schwartz, J.A.
Tamoxifen: an Emerging Preventive. Front. Biosci.;
Potential Molecular Targets for Chemoprevention. 9:2827-2847,
2004 |
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Schwartz, A.G., Prysak, G.M., Murphy, V., Lonardo, F., Pass,
H., Schwartz, J.A., Brooks, S.C.
Nuclear Estrogen Receptor β in Lung Cancer: Expression and
Survival Differences by Sex. Clin. Cancer Res.11 (20):
7280-7287, 2005. |
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Schwartz, J. A.,
The
Significance of Chemicals as Contaminants of Cultured Cell Lines.
Online:
http://scienceboard.net/community/perspectives.173.html 2006 |
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Schwartz, J. A.,
The Republican
War on Science. Online:
http://scienceboard.net/ resources/bookreviews, 2006 |
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Lectures
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