PMID- 16443261
OWN - NLM
STAT- MEDLINE
DCOM- 20060829
LR  - 20211203
IS  - 0090-8258 (Print)
IS  - 0090-8258 (Linking)
VI  - 102
IP  - 2
DP  - 2006 Aug
TI  - Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro 
      on growth and apoptosis of human cancer cells.
PG  - 292-9
AB  - OBJECTIVE: Interactions between estrogen receptor signaling and the PI3K/Akt 
      pathway are present in estrogen-dependent cancer cells. Therapeutical inhibition 
      of each of these pathways has been proven to exert antitumoral effects. 
      Inhibition of mammalian target of rapamycin (mTOR), a downstream target of Akt, 
      is able to restore tamoxifen response in tamoxifen-resistant breast cancer cells. 
      Given that Akt and mTOR phosphorylation also is frequently detected in ovarian 
      and endometrial cancer, we intended to find out to what extent mTOR inhibitor 
      RAD001 (everolimus) and tamoxifen add to each other's effects on growth and 
      apoptosis of cancer cell lines derived from these tissues when given 
      concomitantly. METHODS: OVCAR-3 and SK-OV-3 ovarian cancer cells, HEC-1A 
      endometrial adenocarcinoma cells and MCF-7 breast cancer cells were treated with 
      different concentrations of mTOR inhibitor RAD001 alone or in combination with 
      4-OH tamoxifen. Relative numbers of viable cells were assessed by means of the 
      resazurin-based Cell Titer Blue assay, cellular apoptosis was examined by 
      measurement of activated caspases 3 and 7 by means of the luminometric 
      Caspase-Glo assay. RESULTS: Treatment with RAD001 resulted in growth inhibition 
      of all employed cancer cell lines in a dose-dependent manner, and SK-OV-3 ovarian 
      cancer cells proved to be most sensitive to this drug. Moreover, we report the 
      observation of additive, but not synergistical growth inhibitory effects of a 
      combination treatment with RAD001 and 4-OH TAM on SK-OV-3 and OVCAR-3 ovarian 
      cancer cells and MCF-7 breast cancer cells in vitro, whereas no such effect was 
      observed in HEC-1A endometrial adenocarcinoma cells. Combination treatment with 
      both drugs was demonstrated to be superior to single treatment with lower 
      concentrations (0.1 and 1 nM) of RAD001 or standard concentrations of 4-OH TAM. 
      Furthermore, RAD001 increased the apoptotic effect triggered by high 4-OH TAM 
      concentrations in SK-OV-3 ovarian cancer cells. CONCLUSION: Combination treatment 
      with RAD001 and 4-OH TAM in vitro exerts an additive antitumoral effect on 
      ovarian cancer cells and MCF-7 breast cancer cells. The significance of these 
      data in the clinical situation has to be evaluated in further studies.
FAU - Treeck, Oliver
AU  - Treeck O
AD  - Department of Obstetrics and Gynecology, University Regensburg, Caritas Hospital 
      St. Josef, Landshuter Strasse 65, 93053 Regensburg, Germany. 
      otreeck@caritasstjosef.de
FAU - Wackwitz, Birgit
AU  - Wackwitz B
FAU - Haus, Ulrike
AU  - Haus U
FAU - Ortmann, Olaf
AU  - Ortmann O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060126
PL  - United States
TA  - Gynecol Oncol
JT  - Gynecologic oncology
JID - 0365304
RN  - 0 (RNA, Messenger)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - 17197F0KYM (afimoxifene)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis/drug effects
MH  - Breast Neoplasms/*drug therapy/pathology
MH  - Cell Growth Processes/drug effects
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor
MH  - Drug Synergism
MH  - Endometrial Neoplasms/*drug therapy/pathology
MH  - Everolimus
MH  - Female
MH  - Humans
MH  - Ovarian Neoplasms/*drug therapy/pathology
MH  - Protein Kinases/biosynthesis/genetics
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Sirolimus/administration & dosage/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tamoxifen/administration & dosage/analogs & derivatives
EDAT- 2006/01/31 09:00
MHDA- 2006/08/30 09:00
CRDT- 2006/01/31 09:00
PHST- 2005/09/05 00:00 [received]
PHST- 2005/11/30 00:00 [revised]
PHST- 2005/12/13 00:00 [accepted]
PHST- 2006/01/31 09:00 [pubmed]
PHST- 2006/08/30 09:00 [medline]
PHST- 2006/01/31 09:00 [entrez]
AID - S0090-8258(05)01121-2 [pii]
AID - 10.1016/j.ygyno.2005.12.019 [doi]
PST - ppublish
SO  - Gynecol Oncol. 2006 Aug;102(2):292-9. doi: 10.1016/j.ygyno.2005.12.019. Epub 2006 
      Jan 26.