An easy, rapid and objective mathematical method to identify fatty acid synthase (oncogenic antigen-519) modulators with potential anticancer value.
Fatty acid synthase (FASN) is a novel druggable target for metabolically treating and preventing human malignancies. We envisioned that if loss of sensitivity to C75 (a slow-binding FASN inhibitor) occurs in parallel with loss of FASN expression and/or activity, a mathematical assessment of the nature of the interaction between investigational FASN modulators and C75 may predict the ability of experimental compounds to regulate FASN. We statistically compared the arithmetical sums of the anti-proliferative effects obtained when FASN modulators and C75 were used as single agents to those observed experimentally when agents were actually combined in a sequential schedule (i.e., FASN modulator-->C75). A reduced sensitivity to C75 (antagonism) occurred when compounds down-regulated FASN activity/expression, while an enhanced C75 efficacy (synergism) was found following exposure to FASN up-regulators. This "C75-sensitivity test" might offer an easy, rapid and objective method to identify FASN inhibitors with potential anticancer value in human cancer.
Lupu
Ruth
R
Department of Medicine, Northwestern University Feinberg School of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA. r-lupu@northwestern.edu
Colomer
Ramón
R
Menéndez
Javier A
JA
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054890:Fatty Acid Synthase, Type I / Q000737:chemistry / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D034622:RNA Interference
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D015107:4-Butyrolactone