TY - JOUR
T1 - Indomethacin lowers the threshold thermal exposure for hyperthermic radiosensitization and heat-shock inhibition of ionizing radiation-induced activation of NF-κB
AU - Locke, J. E.
AU - Bradbury, C. M.
AU - Wei, S. J.
AU - Shah, S.
AU - Rene, L. M.
AU - Clemens, R. A.
AU - Roti, J. Roti
AU - Horikoshi, N.
AU - Gius, D.
N1 - Funding Information:
D.G. was supported by grants from the National Institutes of Health (1 K08 CA7020126and-PO1 CA765) a5dtnhe5American Cancer Society (ACS-IRG-58-01430an-dACS RPG-00-2209--TB1E). J.R.R. was supported by grants from the National Institute of Health (RO1 CA41839andPO1 CA765. J.)5.EL.5wassupported by a Fellowship grant from the Radiological Society of North American. J.E.L. and C.M.B. contributed equally to the paper.
PY - 2002
Y1 - 2002
N2 - Purpose: It is well established that salicylate and several other non-steroidal anti-inflammatory agents (NSAID), including indomethacin, can activate the heat-shock response, albeit at high concentrations. This is significant since heat shock significantly alters the cellular cytotoxic response to ionizing radiation (IR). It was previously shown that heat shock, as well as NSAIDs, inhibits IR-induced activation of NF-κB and that NF-κB protects against IR-induced cytotoxicity. Hence, it is hypothesized that pretreatment with indomethacin before heating will lower the temperature and heating times required to inhibit the activation of NF-κB and induce significant hyperthermic radiosensitization. Materials and methods: Experiments were performed in HeLa cell lines and the DNA-binding activity was determined by EMSA. Cellular radiosensitivity was determined by clonogenic assay. Results: HeLa cells pretreated with indomethacin showed a decrease in the temperature-time combination necessary to inhibit IR-induction of NF-κB DNA binding. In addition, clonogenic cell survival assays using identical conditions showed an indomethacin dose-dependent enhancement of hygerthermic radiosensitization. Thus, similar concentrations of indomethacin both lowered the threshold thermal exposure to inhibit activation of NF-κB DNA-binding and increased the sensitivity of tumour cells to hyperthermic radiosensitization-induced cytotoxicity. In HeLa cells treated with N-α-tosylphenylalanyl-chloromethyl ketone (TPCK), a serine protease inhibitor that blocks activation of NF-κB, an increase in radiosensitivity was observed. Interestingly, no additional cell killing was observed when heat shock was added to cells treated with TPCK before IR, suggesting a possible common cytotoxic pathway. Conclusions: The results demonstrate that indomethacin lowers the temperature-time conbination necessary to induce several physiological processes associated with the heat-shock response. Furthermore, NSAID may be potential adjuvants in improving the clinical effectiveness of hyperthermia in radiation therapy.
AB - Purpose: It is well established that salicylate and several other non-steroidal anti-inflammatory agents (NSAID), including indomethacin, can activate the heat-shock response, albeit at high concentrations. This is significant since heat shock significantly alters the cellular cytotoxic response to ionizing radiation (IR). It was previously shown that heat shock, as well as NSAIDs, inhibits IR-induced activation of NF-κB and that NF-κB protects against IR-induced cytotoxicity. Hence, it is hypothesized that pretreatment with indomethacin before heating will lower the temperature and heating times required to inhibit the activation of NF-κB and induce significant hyperthermic radiosensitization. Materials and methods: Experiments were performed in HeLa cell lines and the DNA-binding activity was determined by EMSA. Cellular radiosensitivity was determined by clonogenic assay. Results: HeLa cells pretreated with indomethacin showed a decrease in the temperature-time combination necessary to inhibit IR-induction of NF-κB DNA binding. In addition, clonogenic cell survival assays using identical conditions showed an indomethacin dose-dependent enhancement of hygerthermic radiosensitization. Thus, similar concentrations of indomethacin both lowered the threshold thermal exposure to inhibit activation of NF-κB DNA-binding and increased the sensitivity of tumour cells to hyperthermic radiosensitization-induced cytotoxicity. In HeLa cells treated with N-α-tosylphenylalanyl-chloromethyl ketone (TPCK), a serine protease inhibitor that blocks activation of NF-κB, an increase in radiosensitivity was observed. Interestingly, no additional cell killing was observed when heat shock was added to cells treated with TPCK before IR, suggesting a possible common cytotoxic pathway. Conclusions: The results demonstrate that indomethacin lowers the temperature-time conbination necessary to induce several physiological processes associated with the heat-shock response. Furthermore, NSAID may be potential adjuvants in improving the clinical effectiveness of hyperthermia in radiation therapy.
UR - http://www.scopus.com/inward/record.url?scp=0036086261&partnerID=8YFLogxK
U2 - 10.1080/095530002317577312
DO - 10.1080/095530002317577312
M3 - Article
C2 - 12065054
AN - SCOPUS:0036086261
SN - 0955-3002
VL - 78
SP - 493
EP - 502
JO - International Journal of Radiation Biology
JF - International Journal of Radiation Biology
IS - 6
ER -