Different fatty acid metabolism effects of (-)-epigallocatechin-3-gallate and C75 in adenocarcinoma lung cancer.

Abstract

BACKGROUND:

Fatty acid synthase (FASN) is overexpressed and hyperactivated in several human carcinomas, including lung cancer. We characterize and compare the anti-cancer effects of the FASN inhibitors C75 and (-)-epigallocatechin-3-gallate (EGCG) in a lung cancer model.

METHODS:

We evaluated in vitro the effects of C75 and EGCG on fatty acid metabolism (FASN and CPT enzymes), cellular proliferation, apoptosis and cell signaling (EGFR, ERK1/2, AKT and mTOR) in human A549 lung carcinoma cells. In vivo, we evaluated their anti-tumour activity and their effect on body weight in a mice model of human adenocarcinoma xenograft.

RESULTS:

C75 and EGCG had comparable effects in blocking FASN activity (96,9% and 89,3% of inhibition, respectively). In contrast, EGCG had either no significant effect in CPT activity, the rate-limiting enzyme of fatty acid β-oxidation, while C75 stimulated CPT up to 130%. Treating lung cancer cells with EGCG or C75 induced apoptosis and affected EGFR-signaling. While EGCG abolished p-EGFR, p-AKT, p-ERK1/2 and p-mTOR, C75 was less active in decreasing the levels of EGFR and p-AKT. In vivo, EGCG and C75 blocked the growth of lung cancer xenografts but C75 treatment, not EGCG, caused a marked animal weight loss.

CONCLUSIONS:

In lung cancer, inhibition of FASN using EGCG can be achieved without parallel stimulation of fatty acid oxidation and this effect is related mainly to EGFR signaling pathway. EGCG reduce the growth of adenocarcinoma human lung cancer xenografts without inducing body weight loss. Taken together, EGCG may be a candidate for future pre-clinical development.

• Authors: Joana Relat, Adriana Blancafort, Glòria Oliveras, Sílvia Cufí, Diego Haro, Pedro F Marrero, Teresa Puig
• Journal: BMC cancer (BMC Cancer) Vol. 12 Pg. 280 (Jul 06 2012) ISSN: 1471-2407 [Electronic] England
• PMID: 22769244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• Catechin
• epigallocatechin gallate
• Carnitine O-Palmitoyltransferase
• Fatty Acid Synthases
• 4-Butyrolactone

Topics

• 4-Butyrolactone (analogs & derivatives, pharmacology)
• Adenocarcinoma (drug therapy, enzymology, metabolism, pathology)
• Adenocarcinoma of Lung
• Analysis of Variance
• Animals
• Apoptosis (drug effects)
• Carnitine O-Palmitoyltransferase (metabolism)
• Catechin (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Fatty Acid Synthases (antagonists & inhibitors, metabolism)
• Fatty Acids (metabolism)
• Female
• Humans
• Lung Neoplasms (drug therapy, enzymology, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphorylation (drug effects)
• Random Allocation
• Signal Transduction (drug effects)
• Weight Loss (drug effects)
• Xenograft Model Antitumor Assays