Most cancer chemotherapeutic agents used in the clinic target rapidly-dividing cells which are found n the outer layers of solid tumors. In contrast, the more centrally located cells, which metabolize anaerobically difficult to treat because of their slower growth. Hence, they display a form of multidrug resistance to a wide range anti-cancer agents. Anaerobiosis, however, provides a natural window of selectivity for agents which interfere glycolysis, which is the central theme of this application. Through this proposal we intend to obtain information to stimulate new initiatives in cancer chemotherapy to exploit the hypersensitivity of slow-grow anaerobic-metabolizing tumor cells, with inhibitors of glycolysis for their eventual use in patients. Three distinct tumor cell models have been developed to examine this natural phenomenon and all appear to be hypersensitive to glycolytic inhibitors. Cell Model A represents tumor cells treated at a d rhodamine 123 which specifically uncouples ATP synthesis from electron transport; Cell Model B are p0 cells have lost their mitochondrial DNA and therefore cannot undergo oxidative phosphorylation; and Cell Mc denotes tumor cells in an anaerobic environment, either by exposure to hypoxic conditions (nitrogen) or by giving them as spheroids. Our preliminary data suggest that Cell Models A & B are hypersensitive to 2-deoxyglu known inhibitor of glycolysis. Moreover, in vivo data with cell model A, indicate that cures of tumors can be ac which will be confirmed and further explored here. A variety of tumor cell types, with different forms of MDR, will be used in this proposal. A number of diverse techniques will be employed here which include: clonogenic survival, growth inhibitory assays, lactic analysis, spheroid culture, mitochondrial respiratory assays, fluorescence microscopy, HPLC and human xenograph mice. In addition, new inhibitors of glycolysis will be synthesized and tested in our three cell models. More series of simple cationic compounds which localize in mitochondria, will be utilized to explore how: (a) bl mitochondrial function leads to hypersensitization of tumor cells to glycolytic inhibitors and (b) how they may selectively kill leukemic cells. Our long-term goal is to use glycolytic inhibitors, in conjunction with standard chemotherapy, to enhance its efficacy by selectively killing the anaerobic, slow-growing tumor cells found inner core of solid tumors which are usually the most resistant and consequently the most difficult to eradicate.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037109-14
Application #
6512472
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
1983-07-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
14
Fiscal Year
2002
Total Cost
$310,320
Indirect Cost
Name
University of Miami School of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Philips, Katherine B; Kurtoglu, Metin; Leung, Howard J et al. (2014) Increased sensitivity to glucose starvation correlates with downregulation of glycogen phosphorylase isoform PYGB in tumor cell lines resistant to 2-deoxy-D-glucose. Cancer Chemother Pharmacol 73:349-61
Xi, Haibin; Kurtoglu, Metin; Lampidis, Theodore J (2014) The wonders of 2-deoxy-D-glucose. IUBMB Life 66:110-21
Sullivan, Elizabeth J; Kurtoglu, Metin; Brenneman, Randall et al. (2014) Targeting cisplatin-resistant human tumor cells with metabolic inhibitors. Cancer Chemother Pharmacol 73:417-27
Xi, Haibin; Barredo, Julio C; Merchan, Jaime R et al. (2013) Endoplasmic reticulum stress induced by 2-deoxyglucose but not glucose starvation activates AMPK through CaMKK? leading to autophagy. Biochem Pharmacol 85:1463-77
Liu, Huaping; Kurtoglu, Metin; Cao, Yenong et al. (2013) Conversion of 2-deoxyglucose-induced growth inhibition to cell death in normoxic tumor cells. Cancer Chemother Pharmacol 72:251-62
Leung, Howard J; Duran, Elda M; Kurtoglu, Metin et al. (2012) Activation of the unfolded protein response by 2-deoxy-D-glucose inhibits Kaposi's sarcoma-associated herpesvirus replication and gene expression. Antimicrob Agents Chemother 56:5794-803
Pina, Y; Decatur, C; Murray, Tg et al. (2011) Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LH(BETA)T(AG) retinal tumors. Clin Ophthalmol 5:337-43
Xi, Haibin; Kurtoglu, Metin; Liu, Huaping et al. (2011) 2-Deoxy-D-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. Cancer Chemother Pharmacol 67:899-910
Houston, Samuel K; Pina, Yolanda; Murray, Timothy G et al. (2011) Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LH(BETA)T(AG) retinoblastoma tumors. Clin Ophthalmol 5:129-37
Kurtoglu, Metin; Philips, Katherine; Liu, Huaping et al. (2010) High endoplasmic reticulum activity renders multiple myeloma cells hypersensitive to mitochondrial inhibitors. Cancer Chemother Pharmacol 66:129-40

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