Low-dose fractionated radiation potentiates the effects of Paclitaxel in wild-type and mutant p53 head and neck tumor cell lines.
This study was designed to: (a) evaluate the induction of hyper-radiation sensitivity (HRS), a phenomenon observed at low doses of radiation (<1 Gy); (b) compare the potentiating effects of single dose radiation (2 Gy) versus the effect of low-dose fractionated radiation (LDFRT; <1 Gy) on Paclitaxel; and (c) understand the molecular mechanism of LDFRT-mediated chemo-potentiating effects, in wild-type p53 SCC-61 and p53 mutant SQ-20B head and neck squamous cell carcinoma cell lines. Both cell lines exhibited the HRS phenomenon at low radiation doses. Compared with SCC-61 cells, SQ-20B cells were resistant to radiation and Paclitaxel alone. A significant enhancement of radiation sensitization by Paclitaxel (0.5 or 1 nM) was observed in both cell lines. Chemo-potentiation of Paclitaxel by single 2-Gy radiation was observed in SCC-61 cells but not in SQ-20B cells. However, LDFRT (0.5 Gy in four fractions) significantly chemo-potentiated the effect of Paclitaxel in both cell lines. The cell cycle regulator p53 and its target genes p21(waf1/cip1) and BAX were induced in SCC-61 cells treated with 2 Gy, Paclitaxel, or in combination, but not in SQ-20B cells. These treatments elevated the antiapoptotic BCL-2 protein in SQ-20B cells but not in SCC-61 cells. Interestingly, LDFRT treatment in both cell lines with or without Paclitaxel down-regulated nuclear factor kappa B activity and BCL-2 protein expression and simultaneously up-regulated BAX protein. These findings strongly suggest that LDFRT (at these doses, HRS phenomenon is observed) can be used in combination with Paclitaxel to overcome the antiapoptotic effects of BCL-2 and nuclear factor kappa B.
Dey
Swatee
S
Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
Spring
Paul M
PM
Arnold
Suzanne
S
Valentino
Joseph
J
Chendil
Damodaran
D
Regine
William F
WF
Mohiuddin
Mohammed
M
Ahmed
Mansoor M
MM
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis; D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000532:radiotherapy*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel