Pioglitazone, a ligand for peroxisome proliferator-activated receptor-gamma acts as an inhibitor of colon cancer liver metastasis.
BACKGROUND
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the steroid receptor superfamily. Liganded PPARgamma can inhibit cancer cell proliferation. The in vitro and in vivo inhibitory effect of the synthetic ligands, ciglitazone (CGZ) and pioglitazone (PGZ), on human colon cancer was investigated.


METHODS
Cell proliferation and the expression of PPARgamma, cyclooxygenase (COX)-2 and cyclin D1 were assessed in colon cancer cells treated with CGZ or PGZ. After subcutaneous or splenic inoculation of severe combined immunodeficient (SCID) mice using colon cancer HT-29 and SW480 cells, PGZ was administered orally and tumor growth inhibition was assessed by xenograft volume. The COX-2, cyclin D1 and PPARgamma expression in the HT-29 cells was evaluated.


RESULTS
Cultured HT-29 and SW480 cells expressed PPARgamma and proliferation was inhibited by CGZ and PGZ. Oral PGZ inhibited xenograft tumor growth and liver metastases in the SCID mouse and suppressed expression of COX-2 and cyclin D1 in HT-29 cells.


CONCLUSIONS
PGZ down-regulates COX-2 and cyclin D1 and inhibits colon cancer proliferation and liver metastasis, making PPARgamma a candidate target for the treatment/prevention of colon cancer metastasis.
Takano
Shota
S
Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan.
Kubota
Tetsuro
T
Nishibori
Hideki
H
Hasegawa
Hirotoshi
H
Ishii
Yoshiyuki
Y
Nitori
Nobuhiro
N
Ochiai
Hiroki
H
Okabayashi
Koji
K
Kitagawa
Yuko
Y
Watanabe
Masahiko
M
Kitajima
Masaki
M
D000818:Animals; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D047495:PPAR gamma / Q000096:biosynthesis / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D019938:Cyclin D1; D051546:Cyclooxygenase 2; C039671:ciglitazone; D000077205:Pioglitazone