Enhanced cell killing induced by the combination of radiation and the heat shock protein 90 inhibitor 17-allylamino-17- demethoxygeldanamycin: a multitarget approach to radiosensitization.
OBJECTIVE
Current strategies for tumor cell radiosensitization focus on a target-based approach. However, the radioresponse of a tumor cell is influenced by a wide variety of signaling molecules existing in a number of different survival pathways. Therefore, in an attempt to increase the probability and/or degree of radiosensitization, we have begun to investigate a multitarget approach using the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG).


METHODS
The effect of 17AAG on the levels of three proteins (Raf-1, ErbB2, and Akt) previously implicated in the regulation of radiosensitivity was determined in four human tumor cell lines. Tumor cell survival after exposure to corresponding concentrations of 17AAG combined with clinically relevant doses of X-rays was then evaluated using a clonogenic assay. The radiosensitivity of a nonimmortalized, normal fibroblast cell line was also determined after exposure to 17AAG.


RESULTS
Exposure to nanomolar concentrations of 17AAG reduced the levels of the three radiosensitivity-associated proteins in a cell type manner. Using corresponding concentrations, 17AAG enhanced the radiosensitivity of each of the tumor cell lines with enhancement factors ranging from 1.3 to 1.7. The enhancement appeared to be related to the number of radioresponse-regulatory proteins affected. In contrast to the tumor cell lines, 17AAG had no effect on the radiosensitivity of a normal, nonimmortalized human fibroblast cell line.


CONCLUSIONS
These data suggest that heat shock protein 90 may be an appropriate target for selectively enhancing the radiosensitivity of tumor cells over normal cells. Furthermore, they illustrate the potential of a multitarget approach to radiosensitization.
D016227:Benzoquinones; D002453:Cell Cycle; D016923:Cell Death; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015151:Immunoblotting; D047029:Lactams, Macrocyclic; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011878:Radiotherapy / Q000379:methods*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011838:Radiation-Sensitizing Agents; D017828:Rifabutin; C112765:tanespimycin