- 作者：Keisuke ; Asakura M.D.&lowast ; ; ; &dagger ; ; Yotaro ; Izumi M.D.&lowast ; ; ; yotaroizumi@a2.keio.jp ; Michiko ; Yamamoto M.S.&dagger ; ; Yoshikane ; Yamauchi M.D.&lowast ; ; Kenji ; Kawai M.S.|| ; Akihiko ; Serizawa M.D.¶ ; ; Tomoko ; Mizushima M.S.|| ; Mitsuyo ; Ohmura M.S.&dagger ; ; Masafumi ; Kawamura M.D.&lowast ; ; Masatoshi ; Wakui M.D.§ ; ; Takeshi ; Adachi M.D.# ; Masato ; Nakamura M.D.|| ; ; &lowast ; &lowast ; ; Makoto ; Suematsu M.D.&dagger ; ; Hiroaki ; Nomori M.D.&lowast ;
- 关键词：statins ; mesothelioma ; autophagic changes
- 刊名：Journal of Surgical Research
- 出版年：2011
- 出版时间：October 2011
- 年：2011
- 卷：170
- 期：2
- 页码：e197-e209
- 全文大小：1585 K
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.Materials and Methods
The in?vivo effect of lovastatin was evaluated using an NOD/SCID/¦Ãnull (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.