Metformin enhances anti-tumor effect of L-type amino acid transporter 1 (LAT1) inhibitor.
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.


OBJECTIVE
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.


CONCLUSIONS
By MTT assay, 0.5 mM metformin inhibited proliferation of Ca9-22 cells to 70% of control. In the presence of 100 μM 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.
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan.
Seiji
S
Ueno
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan.
Toru
T
Kimura
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan.
Takashi
T
Yamaga
Japan SLC, Inc., Hamamatsu, Shizuoka, 433-8114, Japan.
Akihiko
A
Kawada
Japan SLC, Inc., Hamamatsu, Shizuoka, 433-8114, Japan.
Toshiaki
T
Ochiai
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan; J-Pharma Co. Ltd., Yokohama, Kanagawa, 230-0046, Japan.
Hitoshi
H
Endou
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan. Electronic address: hsakurai@ks.kyorin-u.ac.jp.
Hiroyuki
H
Sakurai
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics; D007930:Leucine / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
C548172:2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D007004:Hypoglycemic Agents; D027283:Large Neutral Amino Acid-Transporter 1; D046912:Multiprotein Complexes; D014443:Tyrosine; D008687:Metformin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007930:Leucine
AMP-activated protein kinase; Head and neck cancer cells; L-type amino acid transporter 1; Mammalian target of rapamycin; Metformin