Differential effect of selected methylxanthine derivatives on radiosensitization of lung carcinoma cells.
OBJECTIVE
Using caffeine as a reference derivative, this study was performed to investigate how other methylxanthine derivatives, theophylline, 3-isobutyl-methylxanthine and 1,3-dipropyl-7-methylxanthine, sensitize cells to radiation by modifying cell cycle checkpoints and inducing the apoptotic response. The effect of the methylxanthine derivatives was studied in response to gamma and ultraviolet radiation in a human large cell lung carcinoma cell line, null for p53, a normal lung epithelial cell line and the large cell lung carcinoma cell line stably transfected with p53.


METHODS
Effects of theophylline, 3-isobutyl-methylxanthine and 1,3-dipropyl 7-methylxanthine on cell-radiosensitization in comparison to caffeine tested by clonogenic survival assay, MTT assay, ELISA based apoptotic assay, flow cytometry, caspase-3 activity, TUNEL assay, and western blot analysis.


RESULTS
All the derivatives, except 3-isobutyl-methylxanthine, increased tumor cell sensitization to radiation by inducing apoptosis in the p53-null lung cancer cell line. The pattern of cell cycle progression revealed that these derivatives increased the number of cells in G1 phase by abrogating the G2/M checkpoint, directing the cells to apoptose through a p53-independent mechanism. In contrast, 3-isobutyl-methylxanthine was more potent than the other derivatives in radiosensitization of normal lung epithelial cells and the lung carcinoma cells stably transfected with wild-type p53. IBMX increased p53 protein level more than caffeine in lung carcinoma cells stably transfected with wild-type p53.


CONCLUSIONS
Our results suggest that 3-isobutyl-methylxanthine might function through a p53-dependent mechanism.
Malki
A M
AM
Edison Biotechnology Institute, Department of Chemistry and Biochemistry, Ohio University, Athens, 45701, USA.
Gentry
J
J
Evans
S C
SC
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002110:Caffeine / Q000494:pharmacology; D018287:Carcinoma, Large Cell; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D005434:Flow Cytometry; D005720:Gamma Rays; D006801:Humans; D008175:Lung Neoplasms; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013806:Theophylline / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
D011838:Radiation-Sensitizing Agents; D014970:Xanthines; C008514:methylxanthine; D002110:Caffeine; D013806:Theophylline