title: NAD⁺ depletion by APO866 in combination with radiation in a prostate cancer model, results from an in vitro and in vivo study.
abstract: BACKGROUND
  APO866 is a highly specific inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), inhibition of which reduces cellular NAD(+) levels. In this study we addressed the potential of NAD(+) depletion as an anti-cancer strategy and assessed the combination with radiation.
  
  
  METHODS
  The anticipated radiosensitizing property of APO866 was investigated in prostate cancer cell lines PC3 and LNCaP in vitro and in PC3 xenografts in vivo.
  
  
  RESULTS
  We show that APO866 treatment leads to NAD(+) depletion. Combination experiments with radiation lead to a substantial decrease in clonogenic cell survival in PC3 and LNCaP cells. In PC3 xenografts, treatment with APO866 resulted in reduced intratumoral NAD(+) levels and induced significant tumor growth delay. Combined treatment of APO866 and fractionated radiation was more effective than the single modalities. Compared with untreated tumors, APO866 and radiation alone resulted in tumor growth delays of 14 days and 33 days, respectively, whereas the combination showed a significantly increased tumor growth delay of 65 days.
  
  
  CONCLUSIONS
  Our studies show that APO866-induced NAD(+) depletion enhances radiation responses in tumor cell survival in prostate cancer. However, the in vitro data do not reveal a solid cellular mechanism to exploit further clinical development at this moment.
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Shuraila F
authors.initials: SF
authors.lastname: Zerp
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Conchita
authors.initials: C
authors.lastname: Vens
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Ben
authors.initials: B
authors.lastname: Floot
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; Department of Radiation Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address: m.verheij@nki.nl.
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.affiliation: Department of Radiation Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Baukelien
authors.initials: B
authors.lastname: van Triest
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009243:NAD / Q000172:deficiency / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase; D010880:Piperidines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D011838:Radiation-Sensitizing Agents; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase
keywords: APO866; Clonogenic survival; NAD(+) depletion; Preclinical; Radiation