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Investigation into the mechanism of the synergistic interaction between tumor necrosis factor and topoisomerase II inhibitors
Author(s) -
Zhu Weijia
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a387-a
Subject(s) - teniposide , tumor necrosis factor alpha , chromosomal translocation , apoptosis , etoposide , topoisomerase , cytotoxicity , chemistry , nf κb , cytotoxic t cell , cancer research , pharmacology , microbiology and biotechnology , biology , medicine , immunology , biochemistry , in vitro , chemotherapy , gene
Our laboratory was one of the first to discover that the topoisomerase II inhibitors etoposide (VP‐16) and teniposide (VM‐26) synergistically enhanced TNF‐mediated apoptosis of some human tumor cells. To probe the mechanism of cytotoxic synergy, we have examined pro‐ and anti‐apoptotic pathways in cells that show enhanced tumor cell death. ME‐180 human cervical carcinoma cells treated with VP‐16 and VM‐26 showed no significant changes in NF‐κB or IκB protein levels within the first 8h after treatment. NF‐κB translocated into the nucleus following treatment with TNF or TNF and VM‐26, but not with VM‐26 alone, suggesting that the enhancement of TNF cytotoxicity by topoisomerase II inhibitors is not due to a global inhibition of NF‐κB nuclear translocation. When treated TNF alone, a sharp increase in the levels of phospho‐JNK (p‐JNK) was observed at 0.5h, which declined at 1h, and almost disappeared at 2h. Treatment with TNF and VP‐16 caused a second increase in p‐JNK levels at 2h, which was not seen in cells incubated with TNF alone. The translocation of p‐JNK into the nucleus was observed 2h after cells were treated with TNF, but not with VM‐26. However, the combination of TNF and VM‐26 showed increased nuclear translocation of p‐JNK. Future experiments will address the potential role of the second JNK activation event in the enhancement of TNF cytotoxicities by these topoisomerase II inhibitors.