PPAR-gamma agonist increase gefitinib's antitumor activity through PTEN expression.
Gefitinib exhibits antitumor activity in patient with non-small cell lung cancer (NSCLC). However, only 10-20% of patients exhibit clinical response to this drug. The molecular mechanisms underlying gefitinib sensitivity remain unknown. Peroxisome proliferators-activated receptor-gamma (PPAR-gamma) plays roles in the regulation of cellular differentiation and growth. This regulation was mediated by increasing Phosphatase and tensin homologue deleted on chromosome Ten (PTEN) levels. PTEN plays a role in the modulation of the phosphatidylinositol 3-kinase pathway (PI3K), which is involved in cell proliferation and survival. This study investigated the effects of PPAR-gamma agonist (rosiglitazone) on the expression of PTEN, as well as EGFR tyrosine kinase inhibitor (gefitinib)'s antitumor activity in A549 cells. The treatment of A549 cells with rosiglitazone reduced the growth of A549 cells in a dose-dependent manner, and facilitated the anti-proliferative effects of gefitinib. PPAR-gamma and PTEN expression were found to have increased in the gefitinib- and rosiglitazone-treated cells. This suggests that PPAR-gamma agonist (rosiglitazone) potentiated gefitinib's anti-proliferative effects by increased of PTEN expression, and suggest that PPAR-gamma ligands may serve as potential therapeutic agents for NSCLC.
Lee
Sung Yong
SY
Department of Internal Medicine, Korea University, Guro Hospital, Seoul, Republic of Korea.
Hur
Gyu Young
GY
Jung
Ki Hwan
KH
Jung
Hye Cheol
HC
Lee
Sang Yeub
SY
Kim
Je Hyeong
JH
Shin
Chol
C
Shim
Jae Jeong
JJ
In
Kwang Ho
KH
Kang
Kyung Ho
KH
Yoo
Se Hwa
SH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D047495:PPAR gamma / Q000819:agonists; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D000077154:Rosiglitazone; D018709:Statistics, Nonparametric; D045162:Thiazolidinediones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D047495:PPAR gamma; D011799:Quinazolines; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D051059:PTEN Phosphohydrolase; D000077156:Gefitinib