Publications [#177505] of Bruce A Sullenger

Papers Published

1. J Mi, X Zhang, ZN Rabbani, Y Liu, SK Reddy, Z Su, FK Salahuddin, K Viles, PH Giangrande, MW Dewhirst, BA Sullenger, CD Kontos, BM Clary, RNA aptamer-targeted inhibition of NF-kappa B suppresses non-small cell lung cancer resistance to doxorubicin., Molecular therapy : the journal of the American Society of Gene Therapy, vol. 16 no. 1 (January, 2008), pp. 66-73, ISSN 1525-0024 [doi]
   (last updated on 2010/07/15)

   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-kappaB (NF-kappaB) activation. By achieving selective, targeted, and early inhibition of NF-kappaB activity, we demonstrate that NF-kappaB 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-kappaB activation and subsequent chemoresistance is dependent on expression of p53. We also demonstrate that NF-kappaB promotes angiogenesis in the presence of Dox via the hypoxia-inducible factor-1alpha/vascular endothelial growth factor (HIF-1alpha/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.

   Keywords:
   Adenoviridae • Animals • Antibiotics, Antineoplastic • Aptamers, Nucleotide • Carcinoma, Non-Small-Cell Lung • Cell Line, Tumor • Doxorubicin • Drug Delivery Systems* • Drug Resistance, Neoplasm • Genetic Vectors • Humans • Lung Neoplasms • Mice • Mice, Inbred BALB C • Mice, Nude • NF-kappa B • antagonists & inhibitors* • drug therapy* • genetics • genetics* • metabolism • therapeutic use • therapeutic use*