title: Hypoxia and cellular localization influence the radiosensitizing effect of gold nanoparticles (AuNPs) in breast cancer cells.
abstract: Hypoxia exists in all solid tumors and leads to clinical radioresistance and adverse prognosis. We hypothesized that hypoxia and cellular localization of gold nanoparticles (AuNPs) could be modifiers of AuNP-mediated radiosensitization. The possible mechanistic effect of AuNPs on cell cycle distribution and DNA double-strand break (DSB) repair postirradiation were also studied. Clonogenic survival data revealed that internalized and extracellular AuNPs at 0.5 mg/mL resulted in dose enhancement factors of 1.39 ± 0.07 and 1.09 ± 0.01, respectively. Radiosensitization by AuNPs was greatest in cells under oxia, followed by chronic and then acute hypoxia. The presence of AuNPs inhibited postirradiation DNA DSB repair, but did not lead to cell cycle synchronization. The relative radiosensitivity of chronic hypoxic cells is attributed to defective DSB repair (homologous recombination) due to decreased (RAD51)-associated protein expression. Our results support the need for further study of AuNPs for clinical development in cancer therapy since their efficacy is not limited in chronic hypoxic cells.
authors.affiliation: a  Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Cui
authors.forename: Kenneth
authors.initials: K
authors.lastname: Tse
authors.forename: Payam
authors.initials: P
authors.lastname: Zahedi
authors.forename: Shane M
authors.initials: SM
authors.lastname: Harding
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zafarana
authors.forename: David A
authors.initials: DA
authors.lastname: Jaffray
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.forename: Christine
authors.initials: C
authors.lastname: Allen
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D002453:Cell Cycle / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D005260:Female; D006046:Gold / Q000494:pharmacology*; D006801:Humans; D053768:Metal Nanoparticles / Q000008:administration & dosage*; D051135:Rad51 Recombinase / Q000032:analysis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D006046:Gold; D051135:Rad51 Recombinase