PMID- 16540312
OWN - NLM
STAT- MEDLINE
DCOM- 20060626
LR  - 20211203
IS  - 0959-8049 (Print)
IS  - 0959-8049 (Linking)
VI  - 42
IP  - 7
DP  - 2006 May
TI  - Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin increases 
      chemosensitivity of CaSki cells to paclitaxel.
PG  - 934-47
AB  - Paclitaxel, a potent anti-neoplastic agent, has been found to be effective 
      against several tumours, including cervical cancer. However, the exact mechanism 
      underlying the cytotoxic effects of pacitaxel, especially in the 
      survival-signalling pathway, is poorly understood. The aim of this study was to 
      investigate the molecular pathway of the cytotoxic effect of paclitaxel in human 
      cervical cancer cell lines. Four human cervical cancer cell lines were treated 
      for 24 h with various concentration of paclitaxel, and the sensitivity was 
      analysed by an MTT assay. The cell cycle progression and sub-G1 population were 
      analysed by flow cytometry. Apoptosis was further measured by DNA fragmentation 
      and microscope examination. The protein expression was determined by Western blot 
      analysis. Our results showed that HeLa cells demonstrated the highest sensitivity 
      to paclitaxel, whereas CaSki cells showed the lowest. In cervical cancer cells, 
      paclitaxel induced apoptosis through an intrinsic pathway with prior G2/M arrest. 
      In addition, we showed that paclitaxel downregulated the phosphorylation of Akt 
      in both HeLa and CaSki cells. Interestingly, in CaSki cells, which were more 
      suggestive of a resistant phenotype, paclitaxel induced the activation of mTOR as 
      a downstream target of Akt. Pre-treatment with rapamycin inhibited activation of 
      mTOR signalling and significantly enhanced the sensitivity of CaSki cells to 
      paclitaxel by increasing apoptotic cell death. This effect was mediated, at least 
      partly, through caspase activation. Overall, paclitaxel exerts its anti-tumour 
      effects on cervical cancer cells by inducing apoptosis through intrinsic pathway, 
      and rapamycin targeted to mTOR can sensitise paclitaxel-resistant cervical cancer 
      cells.
FAU - Faried, L S
AU  - Faried LS
AD  - Department of Gynecology and Reproductive Medicine, Graduate School of Medicine, 
      Gunma University, Maebashi, Gunma 371-8511, Japan. leri@med.gunma-u.ac.jp
FAU - Faried, A
AU  - Faried A
FAU - Kanuma, T
AU  - Kanuma T
FAU - Nakazato, T
AU  - Nakazato T
FAU - Tamura, T
AU  - Tamura T
FAU - Kuwano, H
AU  - Kuwano H
FAU - Minegishi, T
AU  - Minegishi T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060315
PL  - England
TA  - Eur J Cancer
JT  - European journal of cancer (Oxford, England : 1990)
JID - 9005373
RN  - 0 (Antineoplastic Agents)
RN  - 0 (DNA, Neoplasm)
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  - P88XT4IS4D (Paclitaxel)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Cell Communication
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - DNA, Neoplasm/analysis
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - Drug Screening Assays, Antitumor
MH  - Female
MH  - HeLa Cells
MH  - Humans
MH  - Paclitaxel/*pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Kinases/*drug effects
MH  - Sirolimus/administration & dosage/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Uterine Cervical Neoplasms/*drug therapy/pathology
EDAT- 2006/03/17 09:00
MHDA- 2006/06/27 09:00
CRDT- 2006/03/17 09:00
PHST- 2005/07/20 00:00 [received]
PHST- 2005/12/17 00:00 [revised]
PHST- 2005/12/19 00:00 [accepted]
PHST- 2006/03/17 09:00 [pubmed]
PHST- 2006/06/27 09:00 [medline]
PHST- 2006/03/17 09:00 [entrez]
AID - S0959-8049(06)00099-2 [pii]
AID - 10.1016/j.ejca.2005.12.018 [doi]
PST - ppublish
SO  - Eur J Cancer. 2006 May;42(7):934-47. doi: 10.1016/j.ejca.2005.12.018. Epub 2006 
      Mar 15.