Increased activator protein 1 activity as well as resistance to heat-induced radiosensitization, hydrogen peroxide, and cisplatin are inhibited by indomethacin in oxidative stress-resistant cells
Cm. Bradbury et al., Increased activator protein 1 activity as well as resistance to heat-induced radiosensitization, hydrogen peroxide, and cisplatin are inhibited by indomethacin in oxidative stress-resistant cells, CANCER RES, 61(8), 2001, pp. 3486-3492
It has been established that tumor cells develop resistance to a variety of
therapeutic agents after multiple exposures to these agents/drugs. Many of
these therapeutic agents also appear to increase the activity of transcrip
tion factors, such as activator protein 1 (AP-1), believed to be involved i
n cellular responses to oxidative stress. Therefore, we hypothesized that c
ellular resistance to cancer therapeutic agents may involve the increased a
ctivity of transcription factors that govern resistance to oxidative stress
, such as AP-1. To investigate this hypothesis, a previously characterized
cisplatin, hyperthermia, and oxidative stress-resistant Chinese hamster fib
roblast cell line, OC-14, mas compared to the parental HA-1 cell line. Elec
trophoretic mobility shift and Western blot assays performed on extracts is
olated from OC-14 cells demonstrated a 10-fold increase in constitutive AP-
1 DNA-binding activity as web as increased constitutive c-Fos and c-Jun imm
unoreactive protein relative to HA-1 cells. Treatment of OC-14 cells with i
ndomethacin inhibited constitutive increases in AP-1 DNA binding activity a
nd c-Fos/c-Jun-immunoreactive protein levels. Clonogenic survival assays de
monstrated that pretreatment with indomethacin, at concentrations that inhi
bited AP-1 activity, significantly reduced the resistance of OC-14 cells to
heat-induced radiosensitization, hydrogen peroxide, and cisplatin. These r
esults demonstrate a relationship between increases in AP-I DNA-binding act
ivity and increased cellular resistance to cancer therapeutic agents and ox
idative stress that is inhibited by indomethacin. These results support the
hypothesis that inhibition of AP-I activity with nonsteroidal anti-inflamm
atory drugs, such as indomethacin, may represent a useful adjuvant to cance
r therapy.