Reoxygenation of hypoxic glioblastoma multiforme cells potentiates the killing effect of an interleukin-13-based cytotoxin.
OBJECTIVE
Hypoxia is a cause for resistance to cancer therapies. Molecularly targeted recombinant cytotoxins have shown clinical efficacy in the treatment of patients with primary brain tumors, glioblastoma multiforme, but it is not known whether hypoxia influences their antitumor effect.


METHODS
We have exposed glioblastoma multiforme cells, such as U-251 MG, U-373 MG, SNB-19, and A-172 MG, to either anoxia or hypoxia and then reoxygenated them while treating with an interleukin (IL)-13-based diphtheria toxin (DT)-containing cytotoxin, DT-IL13QM. We measured the levels of immunoreactive IL-13Ralpha2, a receptor that mediates IL-13-cytotoxin cell killing, and the levels of active form of furin, a protease that activates the bacterial toxin portion in a cytotoxin.


RESULTS
We found that anoxia/hypoxia significantly alters the responsiveness of glioblastoma multiforme cells to DT-IL13QM. Interestingly, bringing these cells back to normoxia caused them to become even more susceptible to the cytotoxin than the cells maintained under normoxia. Anoxia/hypoxia caused a highly prominent decrease in the immunoreactive levels of both IL-13R and active forms of furin, and reoxygenation not only restored their levels but also became higher than that in normoxic glioblastoma multiforme cells.


CONCLUSIONS
Our results show that a recombinant cytotoxin directed against glioblastoma multiforme cells kills these cells much less efficiently under anoxic/hypoxic conditions. The reoxygenation brings unexpected additional benefit of making glioblastoma multiforme cells even more responsive to the killing effect of a cytotoxin.
Liu
Tie Fu
TF
Brain Tumor Center of Excellence, Department of Neurosurgery Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Cai
Jiaozhong
J
Gibo
Denise M
DM
Debinski
Waldemar
W
D001932:Brain Neoplasms / Q000378:metabolism* / Q000628:therapy; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D004167:Diphtheria Toxin / Q000494:pharmacology*; D045683:Furin / Q000032:analysis; D005909:Glioblastoma / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*
D003603:Cytotoxins; D004167:Diphtheria Toxin; D000922:Immunotoxins; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D045683:Furin; D010100:Oxygen