Abstract
Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human cancers. Here we report the development of a new series of polyphenolic compounds 5-30 that have been evaluated for their cytotoxic capacity in SK-Br3 cells, a human breast cancer cell line with high FASN expression. The compounds with an IC(50) < 50 μM have been tested for their ability to inhibit FASN activity. Among them, derivative 30 blocks the 90% of FASN activity at low concentration (4 μM), is highly cytotoxic in a broad panel of tumor cells, induces apoptosis, and blocks the activation of HER2, AKT, and ERK pathways. Remarkably, 30 does not activate carnitine palmitoyltransferase-1 (CPT-1) nor induces in mice weight loss, which are the main drawbacks of other previously described FASN inhibitors. Thus, FASN inhibitor 30 may aid the validation of this enzyme as a therapeutic target for the treatment of cancer.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Apoptosis / drug effects
-
Carnitine O-Palmitoyltransferase / metabolism
-
Cell Line, Tumor
-
Drug Screening Assays, Antitumor
-
Enzyme Activation
-
Fatty Acid Synthases / antagonists & inhibitors*
-
Humans
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
Polyphenols / chemical synthesis*
-
Polyphenols / chemistry
-
Polyphenols / pharmacology
-
Proto-Oncogene Proteins c-akt / metabolism
-
Receptor, ErbB-2 / metabolism
-
Signal Transduction / drug effects
-
Structure-Activity Relationship
-
Weight Loss / drug effects
Substances
-
Antineoplastic Agents
-
Polyphenols
-
Carnitine O-Palmitoyltransferase
-
Fatty Acid Synthases
-
ERBB2 protein, human
-
Receptor, ErbB-2
-
Proto-Oncogene Proteins c-akt
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3