RNA Aptamer-targeted Inhibition of NF-κB Suppresses Non-small Cell Lung Cancer Resistance to Doxorubicin.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Mi, J; Zhang, X; Rabbani, ZN; Liu, Y; Reddy, SK; Su, Z; Salahuddin, FK; Viles, K; Giangrande, PH; Dewhirst, MW; Sullenger, BA; Kontos, CD; Clary, BM

Published Date

  • January 2008

Published In

Volume / Issue

  • 16 / 1

Start / End Page

  • 66 - 73

PubMed ID

  • 28192708

Electronic International Standard Serial Number (EISSN)

  • 1525-0024

Digital Object Identifier (DOI)

  • 10.1038/sj.mt.6300320


  • eng

Conference Location

  • United States