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Selective inhibition of fatty acid synthase for lung cancer treatment
Hajime Orita1, Jonathan Coulter, Colleen Lemmon
1Department of Pathology and Johns Hopkins Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Purpose:
Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. However, in vitro use of previous generations of FAS inhibitors has been limited by severe, but reversible, anorexia in treated animals, which is thought to be related to a parallel stimulation of fatty acid oxidation by these agents. This study investigated pharmacologic inhibition of FAS using C93, a rationally designed molecule that inhibits FAS activity without affecting fatty acid oxidation in preclinical models of lung cancer.
Experimental Design:
Activity of C93 on FAS and fatty acid oxidation was evaluated in cultured non-small cell lung cancer (NSCLC) cells. Antineoplastic activity of the compound, given orally or by i.p. injection, was evaluated in s.c. and orthotopic NSCLC xenografts.
Results:
Our experiments confirm that C93 effectively inhibits FAS without stimulating fatty acid oxidation in lung cancer cells. More importantly, C93 significantly inhibits the growth of both s.c. and orthotopic xenograft tumors from human NSCLC cell lines without causing anorexia and weight loss in the treated animals.
Conclusions:
We conclude that inhibition of FAS can be achieved without parallel stimulation of fatty acid oxidation and that inhibition of tumor growth in vivo can be achieved without anorexia and weight loss. Thus, this therapeutic strategy holds promise for clinical treatment of cancers, including non-small cell lung cancer, the leading cause of cancer mortality in the United States and Europe.
Insights
A novel fatty acid synthase (FAS) inhibitor, C93, effectively targets lung cancer cells without causing anorexia or weight loss. This breakthrough offers a promising therapeutic strategy for various cancers, including non-small cell lung cancer.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Fatty acid synthase (FAS) is overexpressed in many human cancers.
- Previous FAS inhibitors caused severe anorexia, limiting their clinical use.
- This anorexia was linked to simultaneous stimulation of fatty acid oxidation.
Purpose of the Study:
- To investigate pharmacologic inhibition of FAS using C93.
- To assess if C93 inhibits FAS without stimulating fatty acid oxidation.
- To evaluate C93's efficacy in preclinical lung cancer models.
Main Methods:
- Assessed C93 activity on FAS and fatty acid oxidation in cultured non-small cell lung cancer (NSCLC) cells.
- Evaluated antineoplastic activity of C93 in s.c. and orthotopic NSCLC xenografts via oral or i.p. administration.
Main Results:
- C93 effectively inhibited FAS without stimulating fatty acid oxidation in lung cancer cells.
- C93 significantly inhibited the growth of both s.c. and orthotopic NSCLC xenograft tumors.
- Treated animals did not experience anorexia or weight loss.
Conclusions:
- FAS inhibition can be achieved without stimulating fatty acid oxidation.
- Tumor growth inhibition in vivo is possible without anorexia and weight loss.
- This therapeutic strategy shows promise for treating cancers, including non-small cell lung cancer.
