Characterization of the combined cellular survival effects of benzoquinone-ansamycins and ionizing radiation.
OBJECTIVE
Benzoquinone-ansamycins were the first compounds characterized with the ability to inhibit the function of heat shock protein 90 and its related family members. We investigated the composite effect of ionizing radiation and of these novel substances on the survival of malignant cells.


METHODS
PC-3M prostate carcinoma cells were treated in vitro with increasing radiation doses in the presence or absence of Hsp90-active and Hsp90-inactive benzoquinone-ansamycins. Cytotoxicity was determined by the crystal violet dissolution assay.


RESULTS
Twenty-four hour treatment with increasing geldanamycin doses (10 nM-1 microM) reduced cellular survival by 1.5 logs for all drug dose levels. Concomitant irradiation with a single fraction of 3 Gy reduced cellular survival by 2 logs, independently of drug dose. The treatment with 100 nM geldanamycin for 24 h combined with ionizing radiation (1-5 Gy) during the first hour of drug exposure reduced cellular survival by 1.5-2 logs depending on radiation-energy dose level, while no changes in cell survival were detectable with equimolar geldampicin, a benzoquinone-ansamycin known not to inhibit Hsp90.


CONCLUSIONS
The inhibition of Hsp90 and the concomitant exposure to ionizing radiation decrease cellular survival of malignant cells. These data contribute to laying the foundation for the translational use of Hsp90 inhibitors in the multimodal therapy of cancer.
Ochel
Hans-Joachim
HJ
Clinic for Radiation Therapy, Medical Faculty, Otto von Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany. hans-joachim.ochel@medizin.uni-magdeburg.de
Gademann
Günther
G
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C004532:quinone