Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library.
For patients with solid tumors, the tolerance of surrounding tissues often limits the dose of radiation that can be delivered. Thus, agents that preferentially increase the cytotoxic effects of radiation toward tumor cells would significantly alter the therapeutic ratio and improve patient survival. Using a high-throughput, unbiased screening approach, we have identified 4'-bromo-3'-nitropropiophenone (NS-123) as a radiosensitizer of human glioma cells in vitro and in vivo. NS-123 radiosensitized U251 glioma cells in a dose-dependent and time-dependent manner, with dose enhancement ratios ranging from 1.3 to 2.0. HT-29 colorectal carcinoma and A549 lung adenocarcinoma cells were also radiosensitized by NS-123 in vitro, whereas NS-123 did not increase the radiation sensitivity of normal human astrocytes or developmental abnormalities or lethality of irradiated Zebrafish embryos. In a novel xenograft model of U251 cells implanted into Zebrafish embryos, NS-123 enhanced the tumor growth-inhibitory effects of ionizing radiation (IR) with no apparent effect on embryo development. Similar results were obtained using a mouse tumor xenograft model in which NS-123 sensitized U251 tumors to IR while exhibiting no overt toxicity. In vitro pretreatment with NS-123 resulted in accumulation of unrepaired IR-induced DNA strand breaks and prolonged phosphorylation of the surrogate markers of DNA damage H2AX, ataxia telangiectasia mutated protein, DNA-dependent protein kinase, and CHK2 after IR, suggesting that NS-123 inhibits a critical step in the DNA repair pathway. These results show the potential of this cell-based, high-throughput screening method to identify novel radiosensitizers and suggest that NS-123 and similar nitrophenol compounds may be effective in antiglioma modalities.
Lally
Brian E
BE
Department of Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.
Geiger
Geoffrey A
GA
Kridel
Steven
S
Arcury-Quandt
Alice E
AE
Robbins
Michael E
ME
Kock
Nancy D
ND
Wheeler
Kenneth
K
Peddi
Prakash
P
Georgakilas
Alexandros
A
Kao
Gary D
GD
Koumenis
Constantinos
C
D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy; D000818:Animals; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D003131:Combined Modality Therapy; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000532:radiotherapy; D019073:HT29 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011427:Propiophenones / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000196:embryology
C524372:4'-bromo-3'-nitropropiophenone; D011427:Propiophenones; D011838:Radiation-Sensitizing Agents