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

Citation
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
Citations number
48
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
61
Issue
8
Year of publication
2001
Pages
3486 - 3492
Database
ISI
SICI code
0008-5472(20010415)61:8<3486:IAP1AA>2.0.ZU;2-#
Abstract
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.