PMID- 27262901
OWN - NLM
STAT- MEDLINE
DCOM- 20170504
LR  - 20211204
IS  - 1347-8648 (Electronic)
IS  - 1347-8613 (Linking)
VI  - 131
IP  - 2
DP  - 2016 Jun
TI  - Metformin enhances anti-tumor effect of L-type amino acid transporter 1 (LAT1) 
      inhibitor.
PG  - 110-7
LID - S1347-8613(16)30038-X [pii]
LID - 10.1016/j.jphs.2016.04.021 [doi]
AB  - BACKGROUND: In many cancer cells, L-type amino acid transporter 1 (LAT1) 
      transports neutral amino acids with bulky side chain, which activate mammalian 
      target of rapamycin (mTOR) to cause cell proliferation. An anti-diabetic drug, 
      metformin, has been shown to activate AMP-activated protein kinase (AMPK), which 
      leads to inhibition of mTOR. LAT1 inhibition in combination with metformin could 
      result in more prominent suppression of mTOR activity. PURPOSE: 
      Anti-proliferative effect of a newly developed LAT1 specific inhibitor JPH203 in 
      combination with metformin is evaluated in 2 head and neck cancer cell lines, 
      Ca9-22 and HEp-2 cells and in nude mice inoculated with Ca9-22 cells. RESULTS AND 
      DISCUSSION: By MTT assay, 0.5 mM metformin inhibited proliferation of Ca9-22 
      cells to 70% of control. In the presence of 100 muM JPH203, proliferation of 
      Ca9-22 cells was inhibited to 60% of control. By combining these 2 drugs, 
      proliferation of Ca9-22 was significantly inhibited to 40% of control. However, 
      this regimen was not very effective against HEp-2 cells. This combination also 
      suppressed in vivo growth of Ca9-22 cells in a xenotransplant model. A 
      combination of anti-LAT1 drug with metformin may be an effective 
      anti-proliferative therapy for certain subsets of cancers.
CI  - Copyright (c) 2016 The Authors. Production and hosting by Elsevier B.V. All rights 
      reserved.
FAU - Ueno, Seiji
AU  - Ueno S
AD  - Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 
      Mitaka, Tokyo, 181-8611, Japan.
FAU - Kimura, Toru
AU  - Kimura T
AD  - Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 
      Mitaka, Tokyo, 181-8611, Japan.
FAU - Yamaga, Takashi
AU  - Yamaga T
AD  - Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 
      Mitaka, Tokyo, 181-8611, Japan.
FAU - Kawada, Akihiko
AU  - Kawada A
AD  - Japan SLC, Inc., Hamamatsu, Shizuoka, 433-8114, Japan.
FAU - Ochiai, Toshiaki
AU  - Ochiai T
AD  - Japan SLC, Inc., Hamamatsu, Shizuoka, 433-8114, Japan.
FAU - Endou, Hitoshi
AU  - Endou H
AD  - Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 
      Mitaka, Tokyo, 181-8611, Japan; J-Pharma Co. Ltd., Yokohama, Kanagawa, 230-0046, 
      Japan.
FAU - Sakurai, Hiroyuki
AU  - Sakurai H
AD  - Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 
      Mitaka, Tokyo, 181-8611, Japan. Electronic address: hsakurai@ks.kyorin-u.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20160510
PL  - Japan
TA  - J Pharmacol Sci
JT  - Journal of pharmacological sciences
JID - 101167001
RN  - 0 
      (2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic 
      acid)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzoxazoles)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Large Neutral Amino Acid-Transporter 1)
RN  - 0 (Multiprotein Complexes)
RN  - 42HK56048U (Tyrosine)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - GMW67QNF9C (Leucine)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use
MH  - Apoptosis/drug effects
MH  - Benzoxazoles/pharmacology/*therapeutic use
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology/therapeutic use
MH  - *Large Neutral Amino Acid-Transporter 1/genetics
MH  - Leucine/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Metformin/pharmacology/*therapeutic use
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Multiprotein Complexes/antagonists & inhibitors
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Tyrosine/*analogs & derivatives/pharmacology/therapeutic use
OTO - NOTNLM
OT  - AMP-activated protein kinase
OT  - Head and neck cancer cells
OT  - L-type amino acid transporter 1
OT  - Mammalian target of rapamycin
OT  - Metformin
EDAT- 2016/06/06 06:00
MHDA- 2017/05/05 06:00
CRDT- 2016/06/06 06:00
PHST- 2016/01/13 00:00 [received]
PHST- 2016/03/17 00:00 [revised]
PHST- 2016/04/24 00:00 [accepted]
PHST- 2016/06/06 06:00 [entrez]
PHST- 2016/06/06 06:00 [pubmed]
PHST- 2017/05/05 06:00 [medline]
AID - S1347-8613(16)30038-X [pii]
AID - 10.1016/j.jphs.2016.04.021 [doi]
PST - ppublish
SO  - J Pharmacol Sci. 2016 Jun;131(2):110-7. doi: 10.1016/j.jphs.2016.04.021. Epub 
      2016 May 10.