Home > Faculty > Dr. Theodore J. Lampidis

Theodore J. Lampidis, Ph.D. Professor of Cell Biology & Anatomy & Member of Sylvester Comprehensive Cancer Center Room 115 Papanicolaou Building, 1550 NW 10th Avenue Telephone: (305) 243-4846 FAX: (305) 243-3414 tlampidi@med.miami.edu

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Curriculum Vitae

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Research Interests

The current research interests of our laboratory derive from our long- term studies on understanding the mechanisms of tumor cell resistance and the structure/function requirements of various chemotherapeutic agents for recognition by p-glycoprotein (P-gp)-mediated multiple drug resistance (MDR). Our work has shown that the mitochondrial agent rhodamine 123 is a substrate for this P-gp drug effluxing pump. Hence it is commonly used to detect this form of MDR in freshly isolated human tumor biopsies for determining which protocols patients may best benefit from.
As an outcome of our studies on mitochondrial agents we realized that tumor cells treated with the uncoupling agent, rhodamine 123, were strikingly similar to the poorly oxygenated (hypoxic) cancer cells located at the inner core of solid tumors. The similarity is that 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, these tumor cells by the nature of their slow growth exhibit a form of MDR, which contributes significantly to chemotherapy failures in the treatment of solid tumors. Anaerobiosis, however, provides a natural window of selectivity for agents that interfere with glycolysis, which is now one of the central theme of our research efforts.
As illustrated in Figure 1 two windows of selectivity exist that can be exploited with inhibitors of glycolysis (2-deoxyglucose (2-DG)) to selectively kill the hypoxic slow growing population of cells found in most solid tumors while sparing the normal aerobic cells: (1) hypoxic tumor cells accumulate more 2-DG than normal aerobic cells and (2) when glycolysis is blocked in hypoxic cells their remaining source of ATP is stopped and therefore they succumb to this treatment. In contrast, even if enough 2-DG accumulates in normal aerobic cells to block glycolysis, by the nature of their mitochondria having access to oxygen they can survive by burning other fuels for energy such as fats and proteins.

 

Fig 1 .Schematic illustration demonstrating different consequences of blocking glycolysis in aerobic vs hypoxic cells. In the aerobic normal cell if glycolysis is inhibited by 2-DG ATP cannot be generated by this pathway. However, since O 2 is available to the mitochondria, amino acids and or fatty acids can act as alternative energy sources for oxidative phosphorylation to take place producing ATP. In contrast, when glycolysis is blocked in the hypoxic tumor cell, other carbon sources cannot be used by mitochondria since O 2 is unavailable and consequently oxidative phosphorylation cannot take place. Thus, when glycolysis is blocked by 2-DG in the hypoxic cell, it has no alternative means for generating ATP and will therefore succumb to this treatment.

Three distinct tumor cell models of simulated hypoxia or anaerobiosis have been developed in our laboratory to examine this natural phenomenon and all show increased lactic acid production ( a measure of glycolysis) and hypersensitivity to glycolytic inhibitors. Model A (Chemical model of “hypoxia”) represents tumor cells treated at a dose of rhodamine 123 which specifically uncouples ATP synthesis from electron transport; Model B (genetic model of “hypoxia”) are Rho 0 cells which have lost their mitochondrial DNA and therefore cannot undergo oxidative phosphorylation, and Model C (environmental model of hypoxia) denotes tumor cells which are growing under reduced levels of oxygen (5 to 0.1 %). We have demonstrated that the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) raises the efficacy of standard chemotherapeutic agents (which target the rapidly growing aerobic tumor cells) by presumably targeting the slow-growing population of solid tumors.

By use of these 3 distinct models of anerobiosis we have recently found and reported that hypoxic inducible factor-1 (HIF-1) confers a level of resistance to glycolytic inhibitors that can be overcome by siRNA specific to HIF-1. These studies have laid the groundwork for subsequent preliminary work in which we find that mTOR inhibitors can be used to increase the sensitivity to 2-DG by down-regulating HIF-1.

Based on our in vitro and in vivo data and with the efforts of Dr. George Tidmarsh of Threshold Pharmaceuticals, Drs. Joseph Rosenblatt and Luis Raez in Miami, a Phase I clinical trial has been initiated in Feb 2004 at the Sylvester Comprehensive Cancer Center in Miami and at the San Antonio Cancer Center in Texas: Protocol #2003121, “ A Phase I dose escalation trial of 2-deoxy-D-glucose alone and in combination with docetaxel in subjects with advanced solid malignancies”. To date (May 2007), 2-DG appears to be non-toxic in 32 patients treated with this protocol.

With our Phase I clinical trial now in progress we are closer to achieving our long-term goal of using glycolytic inhibitors, in conjunction with standard cancer chemotherapy, to enhance its efficacy by selectively killing the anaerobic, slow-growing tumor cells found at the inner core of solid tumors which are usually the most resistant and consequently the most difficult to eradicate.

Recently we have discovered that a percentage of tumor cells under normoxic conditions are killed with 2-DG but not other glycolytic inhibitors. We have uncovered a mechanism of interference with N-linked glycosyaltion that appears to be responsible for this effect. Studies are ongoing to determine the mechanism by which these types of tumor cells are selectively sensitive to the toxic effects of 2-DG under normoxic conditions while most other tumor or normal cells are not. Our long-term goal is to be able to exploit these findings for the eventual clinical use of 2-DG as a single agent with dual activity in interfering with glycosylation in the aerobic portion as well as inhibiting glycolysis in the hypoxic portion of these types of solid tumors thereby killing both malignant cell populations with this relatively non-toxic treatment.

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Selected Publications

Maher,J C, Wangpaichitr, MC, Savaraj, N, Kurtoglu, M and Lampidis , TJ. Hypoxia-Inducible Factor-1 Confers Resistance to the Glycolytic Inhibitor, 2-Deoxy- d-Glucose. Mol Can Therapeutics, Mol Cancer Ther. 2007 Feb;6(2):732-41.

Lampidis, TJ , Kurtoglu, M,  Maher, J,  Liu, HP, Krishan,  A,  Sheft, V,  Szymanski, S, Fokt, I, Rudnicki, WR, Ginalski, K, Lesyng, B and Priebe W. Relative Efficacy of 2-Fluoro-D-glucose > 2-Deoxy-D-glucose > 2-Chloro-D-glucose > 2-Bromo-D-glucose in Blocking Glycolysis and Killing “Hypoxic” Tumor Cells. Cancer Chemoother & Pharmacol. 2006 Mar 23; [Epub ahead of print]

Savaraj N, Wu C, Landy H, Wangpaijit M, Wei M, Kuo T, Robles C, Furst AJ, Lampidis TJ & Feun L. Pro-collagen alpha 1 type I: A Potential Aide in Histopathological Grading of Glioma. Cancer Invest. 2005; 23(7):577-81.

Wu C,Wangpaichitr M, Feun L, Kuo MT, Robles C, Lampidis TJ , and Savaraj N, Overcoming Cisplatin Resistance by mTOR Inhibitor in Lung Cancer. Molecular Cancer, 4:25 doi:10.1186/1476-4598, 2005.

Maher JC, Savaraj N, Priebe W, Liu H, Lampidis TJ. Differential sensitivity to 2-deoxy-D-glucose between two pancreatic cell lines correlates with GLUT-1 expression. Pancreas. 2005,(2):e34-9.

Maschek G, Savaraj N, Priebe W, Braunschweiger P, Hamilton K, Tidmarsh GF, De Young LR, Lampidis TJ. 2-deoxy-D-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo. Cancer Res. 2004,64(1):31-4.

Maher JC, Krishan A, Lampidis TJ. Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol. 2004, 53(2):116-22.Epub 2003 Nov 7.

Savaraj N, Wu C, Wangpaichitr M, Kuo MT, Lampidis T, Robles C, Furst AJ, Feun L. Overexpression of mutated MRP4 in cisplatin resistant small cell lung cancer cell line: collateral sensitivity to azidothymidine. Int J Oncol. 2003, (1):173-9.

Hu YP, Haq B, Carraway KL, Savaraj N, Lampidis TJ. Multidrug resistance correlates with overexpression of Muc4 but inversely with P-glycoprotein and multidrug resistance related protein in transfected human melanoma cells. Biochem Pharmacol. 2003, 65(9):1419-25.

Liu H, Savaraj N, Priebe W, Lampidis TJ. Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy (Model C). Biochem Pharmacol. 2002 Dec 15;64(12):1745-51.

Liu, H. Hu, Savaraj, N. Priebe, W, and Lampidis, TJ. Hypersensitization of Tumor Cells to Glycolytic Inhibitors. Biochemistry, 40:5542-5547, 2001.

Hu, YP, Moraes, C, Savaraj, N, Priebe, W, and Lampidis TJ. r0 Tumor Cells: A model for studying whether mitochondria are targets for Rhodamine 123, Doxorubicin and other drugs. Biochem. Pharm. 60:1897-1905, 2000.

Lampidis, TJ., Kolonias, D., Podona, T., Israel, M., Safa, A., Lotusstein, L., Savaraj, N., Tapiero, H. and Priebe, W. Circumvention of P-gp mdr as a function of anthracyclines lipophilicity and charge. Biochemistry. 36(9):2679-2685, 1997.

Brouty-Boye, D, Kolonias, D, Wu, CJ, Savaraj, N and Lampidis, TJ. Relationship of multidrug resistance to Rhodamine-123 selectivity between carcinoma and normal epithelial cells: Taxol and  Vinblastine modulate drug efflux. Cancer Res. 55:1633-1638, 1995.

Dellinger, M, Pressman, B, Higgenson, C, Kolonias, D, Savaraj, N, Tapiero, H, and Lampidis, T.  Structural requirements of simple organic cations for recognition by multi-drug resistant cells.  Cancer Res. 52:6385-6389, 1992.

Lampidis, TJ, Kolonias, D, Savaraj, N, and Rubin, R.  Cardiostimulatory and anti-arrhythmic activity of tubulin-binding agents.  Proc. Natl. Acad. Sci. USA 89:1256-1260, 1992.

Lampidis, TJ, Castello, C, Giglio, AD, et al.  Relevance of the chemical charge of rhodamine dyes to multiple drug resistance.  Biochem. Pharm. 38:4267-4271, 1989.

Bernal, SB, Lampidis, TJ, McIsaac, B, and Chen, LB.  Anticarcinoma activity in vivo of Rhodamine 123, a mitochondrial·specific dye.  Science 222:169·172, 1983.

Lampidis, TJ, Bernal, SD, Summerhayes, IC, and Chen, LB.  Selective toxicity of Rhodamine 123in carcinoma cells in vitro.  Cancer Res. 43:716·720, 1983.

Bernal, SB, Lampidis, TJ, Summerhayes, IC, and Chen, LB.  Rhodamine 123 selectively reduces clonogenic ability of carcinoma cells in vitro.  Science 218:1117·1119, 1982.

View published research articles by Dr. Lampidis in the National Library of Medicine

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