PMID- 19688827
OWN - NLM
STAT- MEDLINE
DCOM- 20100122
LR  - 20211203
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 126
IP  - 5
DP  - 2010 Mar 1
TI  - Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells 
      through inhibition of cell proliferation and induction of apoptosis.
PG  - 1144-54
LID - 10.1002/ijc.24837 [doi]
AB  - Mammalian target of rapamycin (mTOR) inhibitors modulate signaling pathways 
      involved in cell cycle progression, and recent phase II trials demonstrate 
      activity in patients with endometrial cancer. Our objective was to examine the 
      effects of combination therapy with rapamycin and paclitaxel in endometrial 
      cancer cell lines. Paclitaxel inhibited proliferation in a dose-dependent manner 
      in both cell lines with IC(50) values of 0.1-0.5 nM and 1-5 nM for Ishikawa and 
      ECC-1 cells, respectively. To assess synergy of paclitaxel and rapamycin, the 
      combination index (CI) was calculated by the method of Chou and Talalay. 
      Simultaneous exposure of cells to various doses of paclitaxel in combination with 
      rapamycin (1 nM) resulted in a significant synergistic anti-proliferative effect 
      (CI <1, range 0.131-0.920). Rapamycin alone did not induce apoptosis, but 
      combined treatment with paclitaxel increased apoptosis over that of paclitaxel 
      alone. Treatment with rapamycin and paclitaxel resulted in decreased 
      phosphorylation of S6 and 4E-BP1, two critical downstream targets of the mTOR 
      pathway. Rapamycin decreased hTERT mRNA expression by real-time RT-PCR while 
      paclitaxel alone had no effect on telomerase activity. Paclitaxel increased 
      polymerization and acetylation of tubulin, and rapamycin appeared to enhance this 
      effect. Thus, in conclusion, we demonstrate that rapamycin potentiates the 
      effects of paclitaxel in endometrial cancer cells through inhibition of cell 
      proliferation, induction of apoptosis and potentially increased polymerization 
      and acetylation of tubulin. This suggests that the combination of rapamycin and 
      paclitaxel may be a promising effective targeted therapy for endometrial cancer.
FAU - Shafer, Aaron
AU  - Shafer A
AD  - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 
      University of North Carolina, Chapel Hill, North Carolina 27599-7572, USA.
FAU - Zhou, Chunxiao
AU  - Zhou C
FAU - Gehrig, Paola A
AU  - Gehrig PA
FAU - Boggess, John F
AU  - Boggess JF
FAU - Bae-Jump, Victoria L
AU  - Bae-Jump VL
LA  - eng
GR  - P30 ES010126/ES/NIEHS NIH HHS/United States
GR  - L30 CA136170/CA/NCI NIH HHS/United States
GR  - KL2RR025746/RR/NCRR NIH HHS/United States
GR  - KL2 RR025746/RR/NCRR NIH HHS/United States
GR  - L30 CA136170-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Tubulin)
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  - EC 2.7.7.49 (Telomerase)
RN  - P88XT4IS4D (Paclitaxel)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Endometrial Neoplasms/*pathology
MH  - Female
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Paclitaxel/administration & dosage
MH  - Protein Kinases/drug effects/metabolism
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/administration & dosage
MH  - TOR Serine-Threonine Kinases
MH  - Telomerase/biosynthesis/drug effects
MH  - Tubulin/biosynthesis/drug effects
PMC - PMC2818608
MID - NIHMS163526
COIS- CONFLICT OF INTEREST STATEMENT We, the authors of this manuscript, have no 
      financial or personal relationships to disclose that could inappropriately 
      influence or bias this work.
EDAT- 2009/08/19 09:00
MHDA- 2010/01/23 06:00
PMCR- 2011/03/01
CRDT- 2009/08/19 09:00
PHST- 2009/08/19 09:00 [entrez]
PHST- 2009/08/19 09:00 [pubmed]
PHST- 2010/01/23 06:00 [medline]
PHST- 2011/03/01 00:00 [pmc-release]
AID - 10.1002/ijc.24837 [doi]
PST - ppublish
SO  - Int J Cancer. 2010 Mar 1;126(5):1144-54. doi: 10.1002/ijc.24837.