PMID- 26955235
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20211203
IS  - 1598-6357 (Electronic)
IS  - 1011-8934 (Print)
IS  - 1011-8934 (Linking)
VI  - 31
IP  - 3
DP  - 2016 Mar
TI  - Dual-Blocking of PI3K and mTOR Improves Chemotherapeutic Effects on SW620 Human 
      Colorectal Cancer Stem Cells by Inducing Differentiation.
PG  - 360-70
LID - 10.3346/jkms.2016.31.3.360 [doi]
AB  - Cancer stem cells (CSCs) have tumor initiation, self-renewal, metastasis and 
      chemo-resistance properties in various tumors including colorectal cancer. 
      Targeting of CSCs may be essential to prevent relapse of tumors after 
      chemotherapy. Phosphatidylinositol-3-kinase (PI3K) and mammalian target of 
      rapamycin (mTOR) signals are central regulators of cell growth, proliferation, 
      differentiation, and apoptosis. These pathways are related to colorectal 
      tumorigenesis. This study focused on PI3K and mTOR pathways by inhibition which 
      initiate differentiation of SW620 derived CSCs and investigated its effect on 
      tumor progression. By using rapamycin, LY294002, and NVP-BEZ235, respectively, 
      PI3K and mTOR signals were blocked independently or dually in colorectal CSCs. 
      Colorectal CSCs gained their differentiation property and lost their stemness 
      properties most significantly in dual-blocked CSCs. After treated with 
      anti-cancer drug (paclitaxel) on the differentiated CSCs cell viability, 
      self-renewal ability and differentiation status were analyzed. As a result 
      dual-blocking group has most enhanced sensitivity for anti-cancer drug. Xenograft 
      tumorigenesis assay by using immunodeficiency mice also shows that dual-inhibited 
      group more effectively increased drug sensitivity and suppressed tumor growth 
      compared to single-inhibited groups. Therefore it could have potent anti-cancer 
      effects that dual-blocking of PI3K and mTOR induces differentiation and improves 
      chemotherapeutic effects on SW620 human colorectal CSCs.
FAU - Kim, Min-Jung
AU  - Kim MJ
AUID- ORCID: 0000-0002-5544-8676
AD  - Department of Biotechnology, College of Life Sciences and Biotechnology, Korea 
      University, Seoul, Korea.; Ministry of Food and Drug Safety, Cheongju, Korea.
FAU - Koo, Jeong-Eun
AU  - Koo JE
AUID- ORCID: 0000-0001-6733-2518
AD  - Department of Biotechnology, College of Life Sciences and Biotechnology, Korea 
      University, Seoul, Korea .
FAU - Han, Gi-Yeon
AU  - Han GY
AUID- ORCID: 0000-0001-9825-169X
AD  - Department of Biotechnology, College of Life Sciences and Biotechnology, Korea 
      University, Seoul, Korea .
FAU - Kim, Buyun
AU  - Kim B
AD  - Department of Biotechnology, College of Life Sciences and Biotechnology, Korea 
      University, Seoul, Korea .
FAU - Lee, Yoo-Sun
AU  - Lee YS
AUID- ORCID: 0000-0002-2258-6749
AD  - Department of Biotechnology, College of Life Sciences and Biotechnology, Korea 
      University, Seoul, Korea .
FAU - Ahn, Chiyoung
AU  - Ahn C
AUID- ORCID: 0000-0002-3747-0175
AD  - Ministry of Food and Drug Safety, Cheongju, Korea .
FAU - Kim, Chan-Wha
AU  - Kim CW
AUID- ORCID: 0000-0003-2329-8834
AD  - Department of Biotechnology, College of Life Sciences and Biotechnology, Korea 
      University, Seoul, Korea .
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160217
PL  - Korea (South)
TA  - J Korean Med Sci
JT  - Journal of Korean medical science
JID - 8703518
RN  - 0 (AC133 Antigen)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Chromones)
RN  - 0 (Imidazoles)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 0 (SOX2 protein, human)
RN  - 0 (SOXB1 Transcription Factors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - P88XT4IS4D (Paclitaxel)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - AC133 Antigen/genetics/metabolism
MH  - Animals
MH  - Antineoplastic Agents/pharmacology/therapeutic use
MH  - Cell Differentiation/*drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Chromones/pharmacology/therapeutic use
MH  - Colorectal Neoplasms/drug therapy/metabolism/pathology
MH  - Humans
MH  - Imidazoles/pharmacology/therapeutic use
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Morpholines/pharmacology/therapeutic use
MH  - Neoplastic Stem Cells/cytology/drug effects/metabolism
MH  - Paclitaxel/pharmacology/therapeutic use
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Quinolines/pharmacology/therapeutic use
MH  - SOXB1 Transcription Factors/genetics/metabolism
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC4779859
OTO - NOTNLM
OT  - Cancer Stem Cells
OT  - Differentiation Therapy
OT  - Drug Resistance
OT  - PI3K
OT  - mTOR
COIS- DISCLOSURE: The authors have no potential conflicts of interest to disclose.
EDAT- 2016/03/10 06:00
MHDA- 2016/12/15 06:00
PMCR- 2016/03/01
CRDT- 2016/03/09 06:00
PHST- 2015/08/10 00:00 [received]
PHST- 2015/11/19 00:00 [accepted]
PHST- 2016/03/09 06:00 [entrez]
PHST- 2016/03/10 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
PHST- 2016/03/01 00:00 [pmc-release]
AID - 10.3346/jkms.2016.31.3.360 [doi]
PST - ppublish
SO  - J Korean Med Sci. 2016 Mar;31(3):360-70. doi: 10.3346/jkms.2016.31.3.360. Epub 
      2016 Feb 17.