Development of Ad-mda7/IL-24-resistant lung cancer cell lines.
Many cancers can become resistant to repeated administration of even the most effective therapeutic agents. In developing adenoviral mda-7/IL-24 (Ad-mda-7/IL-24) therapy for lung cancer, we have anticipated this potential clinical problem by attempting to identify the molecular mechanisms of Ad-mda7/IL-24 resistance in several Ad-mda7/IL-24-resistant lung cancer cell lines that we have developed. For the present study, we established four Admda7- resistant cell lines by repeated selection of resistant clones of parental Ad-mda7-sensitive A549 cells: two lines (A549R1 and A549R2) resistant to both adenoviral vector and the mda-7 gene and two (A549R3 and A549R4) resistant to the therapeutic mda-7 gene only. As shown by western blot analysis of several known anti-apoptotic proteins, parental A549 and resistant A549R3 cells expressed similar levels of AKT and phosphorylated AKT (p-AKT), whereas resistant A549R3 and A549R4 cells expressed higher levels of bcl-2 and lower levels of bcl-xL than did their parental cells. As shown by flow-cytometric analysis, treating resistant A549R3 and A549R4 cells with a combination of Ad-mda7 and 17-allyl-amino-17-demethoxygeldanamycin (17AAG) (50 nM) for 48 hours enhanced apoptosis. Together, these in vitro findings indicate that an antiapoptotic mechanism may underlie Ad-mda7 resistance and that such resistance can be overcome by addition of 17AAG. Further investigations along these lines are warranted.
Pataer
Abujiang
A
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. apataer@mdanderson.org
Chada
Sunil
S
Roth
Jack A
JA
Hunt
Kelly K
KK
Swisher
Stephen G
SG
D000256:Adenoviridae / Q000235:genetics; D016227:Benzoquinones / Q000627:therapeutic use; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015316:Genetic Therapy; D006801:Humans; D007378:Interleukins / Q000032:analysis / Q000235:genetics*; D047029:Lactams, Macrocyclic / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000628:therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D011991:Receptors, Virus / Q000032:analysis; D000099180:Interleukin-24
D016227:Benzoquinones; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007378:Interleukins; D047029:Lactams, Macrocyclic; D051057:Proto-Oncogene Proteins c-akt; D011991:Receptors, Virus; D000099180:Interleukin-24; C568771:CLMP protein, human; C112765:tanespimycin