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- Title
RNA Aptamer-targeted Inhibition of NF-κB Suppresses Non-small Cell Lung Cancer Resistance to Doxorubicin.
- Authors
Jing Mi; Xiuwu Zhang; Rabbani, Zahid N.; Yingmiao Liu; Reddy, Srinevas K.; Zhen Su; Salahuddin, Fawzia K.; Viles, Kristi; Giangrande, Paloma H.; Dewhirst, Mark W.; Sullenger, Bruce A.; Kontos, Christopher D.; Clary, Bryan M.
- Abstract
Due to the prevalence of tumor chemoresistance, the clinical response of advanced non-small cell lung cancer (NSCLC) to chemotherapy is poor. We suppressed tumor resistance to doxorubicin (Dox) in A549 cells, a human NSCLC cell line, both in vitro and in vivo in a lung tumor xenograft model, using a novel adenoviral expression system to deliver an RNA aptamer (A-p50) that specifically inhibits nuclear factor-κB (NF-κB) activation. By achieving selective, targeted, and early inhibition of NF-κB activity, we demonstrate that NF-κB plays a critical role in Dox-induced chemoresistance by regulating genes involved in proliferation (Ki-67), response to DNA damage (GADD153), antiapoptosis (Bcl-XL), and pH regulation (CA9). This Dox-induced NF-κB activation and subsequent chemoresistance is dependent on expression of p53. We also demonstrate that NF-κB promotes angiogenesis in the presence of Dox via the hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway, revealing a previously unknown mechanism of NSCLC resistance to Dox. These studies provide important insights into the mechanisms of Dox-induced chemoresistance, and they demonstrate a novel, effective, and clinically practical strategy for interfering with these processes.Molecular Therapy (2007) 16 1, 66–73. doi:10.1038/sj.mt.6300320
- Publication
Molecular Therapy, 2008, Vol 16, Issue 1, p66
- ISSN
1525-0016
- Publication type
Academic Journal
- DOI
10.1038/sj.mt.6300320