Effect of drug-induced cytotoxicity on glucose uptake in Hodgkin's lymphoma cells.
BACKGROUND
In Hodgkin's lymphoma, F-18-fluoro-deoxy-d-glucose positron emission tomography (FDG-PET) is used for staging and response evaluation after chemotherapy. However, drug-mediated downregulation of glucose uptake in viable Hodgkin's lymphoma cells might limit the use of FDG-PET.


METHODS
We analyzed the effect of etoposide on cell viability and uptake of F-18-fluoro-deoxy-D-glucose or the glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) in vitro.


RESULTS
Etoposide induced a dose-dependent cytotoxicity in HDLM-2 cells which was significantly correlated with reduced FDG uptake. However, it also significantly increased the portion of viable cells which did not take up 2-NBDG. Interestingly, etoposide-induced cytotoxicity was mainly mediated via caspase-dependent mechanisms, whereas the cell death induced by deprivation of glucose was mediated via caspase-independent mechanisms.


CONCLUSIONS
Etoposide-mediated reduction of glucose uptake by Hodgkin's lymphoma cells is mainly caused by cell death. In a small fraction of viable cells, etoposide might downregulate glucose transporters and/or hexokinase activity and by that inhibit glucose uptake. This, however, might not lead to false-negative results of response evaluation in Hodgkin's lymphoma patients after chemotherapy, because inhibition of glucose uptake itself seems to be a strong inducer of cell death. Altogether, this study provides important in vitro evidence to clarify the mechanisms by which FDG-PET monitors the effect of anti-cancer treatment in Hodgkin's lymphoma patients.
Banning
Ursula
U
Division of Pediatric Hematology and Oncology, Clinic and Policlinic for Children and Adolescents, University of Leipzig, Leipzig, Germany.
Barthel
Henryk
H
Mauz-Körholz
Christine
C
Kluge
Regine
R
Körholz
Dieter
D
Sabri
Osama
O
D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives* / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000032:analysis; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology*; D005188:False Negative Reactions; D006689:Hodgkin Disease / Q000473:pathology*; D006801:Humans; D009363:Neoplasm Proteins / Q000032:analysis
D000590:Amino Acid Chloromethyl Ketones; D000972:Antineoplastic Agents, Phytogenic; D015853:Cysteine Proteinase Inhibitors; D009363:Neoplasm Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D005047:Etoposide; D003847:Deoxyglucose; D020169:Caspases; D009327:4-Chloro-7-nitrobenzofurazan; C098340:2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose