title: The cytostatic effects of lovastatin on ACC-MESO-1 cells.
abstract: BACKGROUND
  Malignant pleural mesothelioma is known to be widely resistant to therapy, and new treatment strategies are needed. Statins are small molecules that suppress the production of multiple hydrophobic substrates in the mevalonate pathway. Although still controversial, statins may decrease the risk of certain cancers such as colon cancer, lung cancer, and prostate cancer. Since the evaluations of the direct effect of statins on malignant mesothelioma are still few, the present study was done to evaluate the effects of lovastatin on ACC-MESO-1 cells in vivo and to investigate the potential mechanisms involved in vitro.
  
  
  METHODS
  The in vivo effect of lovastatin was evaluated using an NOD/SCID/γnull (NOG) mouse model of human malignant mesothelioma using ACC-MESO-1 cells. Lovastatin was also applied to ACC-MESO-1 cells in vitro and the effects were observed.
  
  
  RESULTS
  Lovastatin administration reduced primary tumor and metastasis in the NOG mouse model of human malignant mesothelioma. In vitro studies showed that lovastatin administration induced cytostatic effects as per reduced cell viability and cell migration in ACC-MESO-1 cells. These effects were suggested to be dependent on autophagic changes rather than apoptosis. Furthermore, induction of autophagic changes by lovastatin in ACC-MESO-1 cells was independent of mTOR, and was considered to be dependent at least in part on Rac/phospholipase C/ inositol 1,4,5-triphosphate axis.
  
  
  CONCLUSIONS
  These results suggest that it may be possible to utilize statins, or other pharmacological agents that are known to induce mTOR-independent autophagy, as an adjunct to standard treatments in malignant mesothelioma.
authors.affiliation: Department of Surgery Division of General Thoracic Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Asakura
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Izumi
authors.forename: Michiko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Yamauchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawai
authors.forename: Akihiko
authors.initials: A
authors.lastname: Serizawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Mizushima
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Ohmura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kawamura
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Wakui
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nomori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009479:Neuropeptides / Q000378:metabolism; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054876:Prenylation / Q000187:drug effects; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D054697:Cytostatic Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D008148:Lovastatin; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein