title: Resveratrol inhibits tumor growth of human neuroblastoma and mediates apoptosis by directly targeting mitochondria.
abstract: OBJECTIVE
  Neuroblastoma is an aggressive childhood disease of the sympathetic nervous system. Treatments are often ineffective and have serious side effects. Because resveratrol, a natural plant product, has been reported to have limited toxicity at chemotherapeutic levels, we investigated its efficacy in the treatment of neuroblastoma as well as its underlying mechanism of action.
  
  
  METHODS
  Resveratrol was tested in mouse xenograft models of human neuroblastoma and in vitro using human cell lines.
  
  
  RESULTS
  Resveratrol inhibited the outgrowth of tumors by as much as 80%. The bioavailability of the drug in serum was in the low micromolar range (2-10 micromol/L) and no accumulation was observed in tumor tissue. When resveratrol levels were increased by peritumor injection, rapid tumor regression occurred. Resveratrol decreased tumor cell viability in vitro by 75% to 90%, resulting from an inhibition of cell proliferation and an induction of apoptosis. Loss of mitochondrial membrane potential was an early response to resveratrol. In addition, resveratrol treatment of isolated mitochondria also led to depolarization, suggesting that the drug may target mitochondria directly. Following depolarization, resveratrol caused the release of cytochrome c and Smac/Diablo from the mitochondria and subsequently the activation of caspase-9 (4- to 8-fold) and caspase-3 (4- to 6-fold).
  
  
  CONCLUSIONS
  These studies indicate that, despite low bioavailability, resveratrol is effective at inhibiting tumor growth. Elevated levels of resveratrol enhance its antitumor potency leading to tumor regression, associated with widespread tumor cell death, the underlying mechanism of which involves the direct activation of the mitochondrial intrinsic apoptotic pathway.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: van Ginkel
authors.forename: Dhruv
authors.initials: D
authors.lastname: Sareen
authors.forename: Lalita
authors.initials: L
authors.lastname: Subramanian
authors.forename: Quintisha
authors.initials: Q
authors.lastname: Walker
authors.forename: Soesiawati R
authors.initials: SR
authors.lastname: Darjatmoko
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Lindstrom
authors.forename: Amol
authors.initials: A
authors.lastname: Kulkarni
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Albert
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Polans
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001682:Biological Availability; D045744:Cell Line, Tumor; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D000077185:Resveratrol; D013267:Stilbenes / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous