title: Resveratrol induces SIRT1- and energy-stress-independent inhibition of tumor cell regrowth after low-dose platinum treatment.
abstract: OBJECTIVE
  To investigate resveratrol (RSV) as a calorie restriction (CR) mimetic potentiator of platinum-based cancer drugs.
  
  
  METHODS
  In ovarian carcinoma cell lines, the potentiating effects of RSV were assessed in sulforhodamine B-based growth assays and clonogenic assays. Flow cytometry was used to detect cell cycle effects, siRNA transfections for determining the involvement of SIRT1, and Western blotting for the assessment of altered protein expression and of autophagy. Intracellular ATP levels were detected with a commercial kit.
  
  
  RESULTS
  Single-dose RSV co-treatment with cisplatin or carboplatin at inefficiently low doses had the clinically interesting effect of preventing regrowth of cancer cells after drug withdrawal. Of three cell lines tested, metastatic cells with low bioenergetic cellular index (i.e., more glycolytic) were particularly sensitive to combination treatment leading to PUMA induction, acute apoptosis, and autophagy. However, inhibition of regrowth and complete loss of clonogenicity was seen also without these events, in other cells. The underlying mechanism(s) was independent of effects reported to underlie the CR-mimetic cancer-preventive potential of RSV. Thus, SIRT1, estrogen receptors, AMPK activation or upregulation of mitobiogenesis, β-F(1)-ATPase or PTEN were not involved, and ATP levels did not decrease.
  
  
  CONCLUSIONS
  RSV is an excellent candidate for potentiation of platinum treatment, rather than a cancer therapeutic drug in its own right. While SIRT1-dependent and lifespan-promoting effects of RSV are well-documented and may dominate in normal cells, the observed potentiation of platinum drugs does not require these mechanisms. We suggest that the responses of cancer cells to RSV differ greatly from those of normal cells.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: My
authors.initials: M
authors.lastname: Björklund
authors.forename: Jeanette
authors.initials: J
authors.lastname: Roos
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gogvadze
authors.forename: Maria
authors.initials: M
authors.lastname: Shoshan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000032:analysis; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology*; D013312:Stress, Physiological
chemical_list: D000970:Antineoplastic Agents; D013267:Stilbenes; D016190:Carboplatin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D002945:Cisplatin; D000077185:Resveratrol