Acetaminophen selectively reduces glioma cell growth and increases radiosensitivity in culture.
Glioblastoma multiforme (GBM) is a highly lethal brain cancer. Using cultures of rodent and human malignant glioma cell lines, we demonstrated that millimolar concentrations of acetylsalicylate, acetaminophen, and ibuprofen all significantly reduce cell numbers after several days of culture. However, their mechanisms of action may vary, as demonstrated by (1) differences in the morphological changes produced by these compounds; (2) varied responses to these drugs with respect to toxicity kinetics; and (3) respective rates of cell proliferation, DNA synthesis, and mitotic index. We studied the effects of acetaminophen on relative cell number further. Evidence is presented that acetaminophen induced cell death by an apoptotic mechanism after a brief burst of mitosis in which cell numbers increased transiently, followed by a reduction in cell number and an increase in DNA fragmentation, as evidenced by terminal deoxytransferase-mediated dUTP-biotin nick end labeling (TUNEL) analysis. Using cultures of adult human brain and embryonic rat brain, we demonstrated that glioma cells were several-fold more sensitive to acetaminophen than normal brain cells in culture. Finally, subtoxic doses of acetaminophen increased the sensitivity of the human glioma cells in culture to ionizing radiation. Taken together, these results suggest that acetaminophen may prove to be a useful therapeutic agent in the treatment of human brain tumors.
Casper
D
D
Department of Neurological Surgey, Montefiore Medical Center, Bronx, NY 10467, USA.
Lekhraj
R
R
Yaparpalvi
U S
US
Pidel
A
A
Jaggernauth
W A
WA
Werner
P
P
Tribius
S
S
Rowe
J D
JD
LaSala
P A
PA
D000082:Acetaminophen / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D001932:Brain Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005909:Glioblastoma / Q000473:pathology*; D005910:Glioma / Q000473:pathology*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008940:Mitotic Index; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006131:Growth Inhibitors; D011838:Radiation-Sensitizing Agents; D000082:Acetaminophen; D001241:Aspirin; D007052:Ibuprofen