Down-regulation of gene transcripts associated with ricin tolerance in human RPMI 2650 cells.
The present study sought to determine if novel therapeutic approaches against ricin intoxication could be identified from human respiratory tract cells selected for increased resistance to this toxin. Initial studies indicated that the RPMI 2650 line was an appropriate model, owing to its sensitivity to ricin. Tolerant cultures were developed by exposing cells to a graded series of ricin concentrations from 6 to 192 pM. This resulted in the generation of cultures whose LC(50) values were increased by up to 4-fold following exposure to up to 96 pM ricin and by up to 6-fold following exposure to up to 192 pM ricin, compared to control cultures. DNA microarrays were employed to determine the gene transcript expression profile of cultures with increased resistance to ricin to investigate which gene products mediate ricin resistance. Transcripts (10) were identified that were greater than 2-fold down-regulated in the cells tolerant to 96 pM ricin, whereas 48 transcripts were seen to be down-regulated in cultures tolerant to 192 pM ricin. Gene transcripts (5) were up-regulated 2-fold or more in the 192 pM tolerant cultures in comparison to unexposed cells. The results indicate that ricin tolerance is the product of complex changes in gene expression profiles, most of which were found to involve down-regulation of transcript expression. It may be possible to modulate the gene expression profiles associated with ricin tolerance for potential therapeutic purposes using drugs and antisense technologies.
Wilkinson
L J
LJ
Biomedical Sciences Department, Dstl Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Duffield
M L
ML
Titball
R W
RW
Lindsay
C D
CD
D002460:Cell Line; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004361:Drug Tolerance / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012276:Ricin / Q000633:toxicity*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics
D002619:Chemical Warfare Agents; D012276:Ricin