Objective: The folic acid analog pemetrexed (PMX) is recommended for the first-line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). However, the mechanisms underlying PMX cytotoxicity in NSCLC remain to be fully explored. Methods: PMX effect was evaluated in a urethane-induced lung adenocarcinoma mouse model. The interaction between PMX and intracellular proteins, particularly peroxisome proliferator-activated receptor gamma (PPAR gamma), was investigated. The role of PPAR gamma in mediating pemetrexed cytotoxicity was investigated using NSCLC cell lines, mouse models and clinical specimens. Results: This study found that PPAR gamma expression was correlated with prolonged progression-free survival in NSCLC patients. PPAR gamma downregulated hypoxanthine-guanine phosphoribosyl transferase (HGPRT), a key enzyme for nucleotide salvage synthesis, thereby sensitizing cells to PMX inhibition on nucleotide de novo synthesis. PMX was also a candidate partial agonist of PPAR gamma, and PMX-activated PPAR gamma bound to NF-kappa B and transcriptionally suppressed the NF-kappa B target gene, c-Myc. PMX inhibited tumor growth by activating PPAR gamma in a urethane-induced lung cancer model characterized by elevated NF-kappa B activity. Conclusion: PPAR gamma improves pemetrexed therapeutic efficacy in non-squamous NSCLC. The cytotoxicity effect of PMX can be synergized by activating PPAR gamma and thereby inhibiting NF-kappa B pathway.
[1]Fudan Univ, Huashan Hosp, Dept Pulm & Crit Care Med, Shanghai 200040, Peoples R China.
[2]Nanjing Univ Chinese Med, Hosp Nanjing 2, Dept TB, Nanjing, Peoples R China.
[3]Navy Med Univ Chinese PLA, Dept Anesthesiol, Changzheng Hosp, Shanghai, Peoples R China.
[4]Shaanxi Prov Second Peoples Hosp, Dept Resp Med, Xian, Peoples R China.
(8.0+极速模式)