title: RNA aptamer-targeted inhibition of NF-kappa B suppresses non-small cell lung cancer resistance to doxorubicin.
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.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA. mi001@duke.edu
authors.forename: Jing
authors.initials: J
authors.lastname: Mi
authors.forename: Xiuwu
authors.initials: X
authors.lastname: Zhang
authors.forename: Zahid N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: Yingmiao
authors.initials: Y
authors.lastname: Liu
authors.forename: Srinevas K
authors.initials: SK
authors.lastname: Reddy
authors.forename: Zhen
authors.initials: Z
authors.lastname: Su
authors.forename: Fawzia K
authors.initials: FK
authors.lastname: Salahuddin
authors.forename: Kristi
authors.initials: K
authors.lastname: Viles
authors.forename: Paloma H
authors.initials: PH
authors.lastname: Giangrande
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Sullenger
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Kontos
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Clary
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D052157:Aptamers, Nucleotide; D016328:NF-kappa B; D004317:Doxorubicin