Effect of drug-induced cytotoxicity on glucose uptake in Hodgkin's lymphoma cells

Eur J Haematol. 2006 Aug;77(2):102-8. doi: 10.1111/j.1600-0609.2006.00675.x. Epub 2006 Jun 23.

Abstract

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Chloro-7-nitrobenzofurazan / analogs & derivatives*
  • 4-Chloro-7-nitrobenzofurazan / metabolism
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Caspases / analysis
  • Cell Death / drug effects
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • Cell Line, Tumor / pathology
  • Cysteine Proteinase Inhibitors / pharmacology
  • Deoxyglucose / analogs & derivatives*
  • Deoxyglucose / metabolism
  • Energy Metabolism / drug effects
  • Etoposide / pharmacology*
  • False Negative Reactions
  • Hodgkin Disease / pathology*
  • Humans
  • Neoplasm Proteins / analysis

Substances

  • Amino Acid Chloromethyl Ketones
  • Antineoplastic Agents, Phytogenic
  • Cysteine Proteinase Inhibitors
  • Neoplasm Proteins
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Etoposide
  • Deoxyglucose
  • Caspases
  • 4-Chloro-7-nitrobenzofurazan
  • 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose