title: Albendazole sensitizes cancer cells to ionizing radiation.
abstract: BACKGROUND
  Brain metastases afflict approximately half of patients with metastatic melanoma (MM) and small cell lung cancer (SCLC) and represent the direct cause of death in 60 to 70% of those affected. Standard of care remains ineffective in both types of cancer with the challenge of overcoming the blood brain barrier (BBB) exacerbating the clinical problem. Our purpose is to determine and characterize the potential of albendazole (ABZ) as a cytotoxic and radiosensitizing agent against MM and SCLC cells.
  
  
  METHODS
  Here, ABZ's mechanism of action as a DNA damaging and microtubule disrupting agent is assessed through analysis of histone H2AX phosphorylation and cell cyle progression. The cytotoxicity of ABZ alone and in combination with radiation therapy is determined though clonogenic cell survival assays in a panel of MM and SCLC cell lines. We further establish ABZ's ability to act synergistically as a radio-sensitizer through combination index calculations and apoptotic measurements of poly (ADP-ribose) polymerase (PARP) cleavage.
  
  
  RESULTS
  ABZ induces DNA damage as measured by increased H2AX phosphorylation. ABZ inhibits the growth of MM and SCLC at clinically achievable plasma concentrations. At these concentrations, ABZ arrests MM and SCLC cells in the G2/M phase of the cell cycle after 12 hours of treatment. Exploiting the notion that cells in the G2/M phase are the most sensitive to radiation therapy, we show that treatment of MM and SCLC cells treated with ABZ renders them more sensitive to radiation in a synergistic fashion. Additionally, MM and SCLC cells co-treated with ABZ and radiation exhibit increased apoptosis at 72 hours.
  
  
  CONCLUSIONS
  Our study suggests that the orally available antihelminthic ABZ acts as a potent radiosensitizer in MM and SCLC cell lines. Further evaluation of ABZ in combination with radiation as a potential treatment for MM and SCLC brain metastases is warranted.
authors.affiliation: The Ronald O, Perelman Department of Dermatology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Kirtesh
authors.initials: K
authors.lastname: Patel
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doudican
authors.forename: Peter B
authors.initials: PB
authors.lastname: Schiff
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Orlow
mesh_terms: D015766:Albendazole / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000556:secondary*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000556:secondary; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D015766:Albendazole
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