The
endocannabinoid anandamide (AEA), a
neurotransmitter was shown to have anti-
cancer effects.
Fatty acid amide hydrolase (FAAH) metabolizes AEA and decreases its anti-tumorigenic activity. In this study, we have analyzed the role of FAAH inhibition in
non-small cell lung cancer (NSCLC). We have shown that FAAH and
CB1 receptor which is activated by AEA are expressed in
lung adenocarcinoma patient samples and NSCLC cell lines A549 and H460. Since the synthetic analogue of
anandamide (
Met-F-AEA) did not possess significant anti-tumorigenic effects, we used
Met-F-AEA in combination with FAAH inhibitor
URB597 which significantly reduced
EGF (
epidermal growth factor)-induced proliferative and chemotactic activities in vitro when compared to anti-tumorigenic activity of
Met-F-AEA alone. Further analysis of signaling mechanisms revealed that
Met-F-AEA in combination with
URB597 inhibits activation of EGFR and its downstream signaling ERK, AKT and
NF-kB. In addition, it inhibited MMP2 secretion and stress fiber formation. We have also shown that the
Met-F-AEA in combination with
URB597 induces G0/G1 cell cycle arrest by downregulating
cyclin D1 and CDK4 expressions, ultimately leading to apoptosis via activation of
caspase-9 and PARP. Furthermore, the combination treatment inhibited
tumor growth in a xenograft nude mouse model system.
Tumors derived from
Met-F-AEA and
URB597 combination treated mice showed reduced EGFR, AKT and ERK activation and MMP2/MMP9 expressions when compared to
Met-F-AEA or
URB597 alone. Taken together, these data suggest in EGFR overexpressing NSCLC that the combination of
Met-F-AEA with FAAH inhibitor resulted in superior therapeutic response compared to individual compound activity alone.