tumor cell biology program - Sylvester Comprehensive Cancer Center

ing of the Xenopus blastula. These studies
on maternal VegT, a T-box transcription
factor, have shown that it is
essential for three important steps in
development. VegT is required for endoderm
specification; the production,
activation, or delivery of the mesoderm
inducer; and for maintaining the
boundary between endoderm and mesoderm.
Their results strongly suggest
that the major mesoderm-inducing signal
is a post-transcriptional event in
Xenopus. Future studies should provide
insights into the genetic pathways operating
to establish some of these organ
systems and may explain specific
birth defects where meso-endodermal
tissue is affected. In addition, the
downstream targets of VegT must play
a role in morphogenesis, as gastrulation
is profoundly disrupted and epiboly inhibited.
Very little is known about the
genes that regulate the regional cellular
movements of gastrulation.
Theodore J. Lampidis, Ph.D.
Professor of Cell Biology
and Anatomy
DESCRIPTION OF RESEARCH
Dr. Lampidis’ research has evolved
since his preliminary work on the
physiology and pharmacology of cultured
cardiac cells. A video/electroniccomputerized
system was developed to
monitor cardiac cell function in vitro.
Using pulsating myocardial cells as a
model, attention was then placed on why
the widely used anti-tumor agent,
Adriamycin, affected the hearts of patients
treated with this drug. This initial
idea led them to the study of drug selectivity
between certain types of tumor and
normal cells and the chemical requirements
of anticancer drugs for reduced
cardiotoxicity and increased tumoricidal
potency.
His research team’s efforts then
turned toward understanding the mechanisms
of drug resistance to mitochondrial
agents such as rhodamine 123 and the
structure/function requirements of various
chemotherapeutic agents for recognition
by p-glycoprotein-mediated
multiple drug resistance (MDR). Molecular
and immunochemical probes of
MDR and other cellular resistance
mechanisms, i.e. MRP, were developed
in his laboratory to detect and study these
phenomena. The researchers found that
chemical charge and lipophilicity play
critical roles in determining whether anticancer
drugs are recognized by tumor
cells expressing these MDR mechanisms.
As an outcome of their studies on
mitochondrial agents, they realized that
tumor cells treated with the uncoupling
agent, rhodamine 123, were strikingly
similar to the poorly oxygenated cancer
cells located at the inner core of solid
tumors. In both conditions the cells similarly
rely exclusively on anaerobic metabolism
for survival. Moreover, cells in
the center of a tumor divide more slowly
than outer growing aerobic cells and consequently
are more resistant to standard
chemotherapeutic agents which target
the more rapidly dividing cells. Thus, by
the nature of their slow growth, these tumor
cells exhibit a form of MDR, which
contributes significantly to chemotherapy
failures in the treatment of solid
tumors.
Anaerobiosis, however, also provides
a natural window of selectivity for agents
that interfere with glycolysis. This concept
forms the basis for his current initiative
of exploiting the natural selectivity
that inhibitors of glycolysis should have
for hypoxic cells that are slowly growing
at the inner core of solid tumors. Dr.
Lampidis believes their background and
work on mitochondrial localizing drugs
and MDR uniquely positions them to
stimulate new initiatives in this promising
area of research.
A long-term research goal for Dr.
Lampidis is the addition of the appropriate
glycolytic inhibitors (which they
are presently designing and synthesizing)
to current clinical protocols, which may
significantly improve the success rate of
cancer chemotherapy. Moreover, studying
how tumor cells react to combinations
of oxidative phosphorylation and
glycolytic inhibitors could lead to the
design of future novel approaches to
more successfully treat cancer.
PUBLICATIONS
Kolonias, D, Podona, T, Savaraj, N,
Gate, L, Cossum, P and Lampidis, TJ.
Comparison of annamycin to adriamycin
in cardiac and MDR tumor cell systems.
Anticancer Research 19:1277, 1999.
Zou, JY, Landy, H, Feun, L, Xu, R,
Lampidis, TJ, Wu, CJ, Furst, AJ, and
Savaraj, N. Correlation of a unique 220-
kd protein with vitamin D sensitivity in
glioma cells. Biochemistry Pharmacology
60:1361, 2000.
Hu, Y, Moraes, CT, Savaraj, N,
Priebe, W and Lampidis, TJ. Rho(0)
tumor cells: a model for studying
whether mitochondria are targets for
rhodamine 123, doxorubicin and other
drugs. Biochemical Pharmacology
60:1897, 2000.
Hiu, H, Hu, YP, Savaraj, N, Priebe,
W and Lampidis, TJ. Hypersensitization
of tumor cells to glycolytic inhibitors.
Biochemistry 40:5542, 2001.
HIGHLIGHTS/DISCOVERIES
• In Model A, which represents osteosarcoma
wild type (wt) cells treated with
agents that inhibit mitochondrial oxidative
phosphorylation (Oxphos) by
interacting with complexes I, III, and
V of the electron transport chain in different
ways, i.e. rhodamine 123 (Rho
123), rotenone, oligomycin, and antimycin
A, all of the agents were found
to hypersensitize wt cells to the glycolytic
inhibitors 2-deoxyglucose and
oxamate.
• In Model B, which are ρ cells that have
lost their mitochondrial DNA and
therefore cannot undergo Oxphos,
were found to be 10 and 4.9 times
more sensitive to 2-deoxyglucose and
oxamate, respectively, than wt cells.
• Lactic acid levels, which are a measure
of anaerobic metabolism, were found
to be >3 times higher in ρ than in wt
cells. Moreover, when wt cells were
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2002