SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M
of anti-cancer drugs for reduced cardiotoxicity
and increased tumoricidal potency.
Dr. Lampidis’ 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 (Pgp)-mediated multiple drug
resistance (MDR). Molecular and immunochemical
probes of MDR and other cellular
resistance mechanisms (i.e., multi-drug resistance-related
protein), were developed to detect
and study these phenomena. He and his colleagues
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, these researchers 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 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
Dr. Lampidis’ 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. His
background and work on mitochondrial localizing
drugs and MDR uniquely position him to
stimulate new initiatives in this promising area of
research.
A long-term goal for Dr. Lampidis is the addition
of the appropriate glycolytic inhibitors
(which are presently being designed and synthesized)
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.
SELECTED PUBLICATIONS
2002
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ .
Hypoxia increases tumor cell sensitivity to glycolytic
inhibitors: a strategy for solid tumor therapy
(Model C). Biochemical Pharmacology 64:1745-
51, 2002.
2003
Savaraj N, Wu, C, Wangpaichitr, M, Kuo, MT,
Lampidis, TJ , Robles, C, Furst, AJ, and Feun, L.
Overexpression of mutated MRP4 in cisplatin
resistant small cell lung cancer cell line: collateral
sensitivity to azidothymidine. International Journal
of Oncology 23:173-79, 2003.
Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and
Lampidis, TJ . Multidrug resistance correlates
with overexpression of Muc4 but inversely with
P-glycoprotein and multidrug resistance related
protein in transfected human melanoma cells.
Biochemical Pharmacology 65:1419-25, 2003.
HIGHLIGHTS/DISCOVERIES
• In 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—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 (2-DG) and oxamate.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 41