Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy

ABSTRACT

Introduction: Cancer cells have increased glycolysis and glutaminolysis. Their third feature is increased de novo lipogenesis. As such, fatty acid (FA) synthesis enzymes are over-expressed in cancer and their depletion causes antitumor effects. As fatty acid synthase (FASN) plays a pivotal role in this process, it is an attractive target for cancer therapy.

Areas covered: This is a review of the lipogenic phenotype of cancer and how this phenomenon can be exploited for cancer therapy using inhibitors of FASN, with particular emphasis on orlistat as a repurposing drug.

Expert opinion: Disease stabilization only has been observed with a highly selective FASN inhibitor used as a single agent in clinical trials. It is too early to say whether the absence of tumor responses other than stabilization results because even full inhibition of FASN is not enough to elicit antitumor responses. The FASN inhibitor orlistat is a ‘dirty’ drug with target-off actions upon at least seven targets with a proven role in tumor biology. The development of orlistat formulations suited for its intravenous administration is a step ahead to shed light on the concept that drug promiscuity can or not be a virtue.

KEYWORDS:

• Orlistat
• fatty acid synthase (FASN)
• malignant lipogenic phenotype
• drug repurposing

Article highlights

• Cancer cells exhibit a lipogenic phenotype

• While normal cells use fatty acids from the diet, cancer the cells are in need of de novo lipogenesis though they can also uptake dietary fatty acids.

• The enzyme fatty acid synthase synthesizes the fatty acid palmitate starting from acetyl-CoA to end up in triacylglycerols and phosphoglycerides.

• FASN is over-expressed in tumor cells and its genetic or pharmacological blockade induces antitumor effects

• The first rationally designed FASN Inhibitor has been tested in phase I and II clinical trials.

• Orlistat a known FASN inhibitor has also target-off effects upon at least seven cancer targets.

• Efforts by repositioning orlistat as a cancer drug has advanced up to the development of intravenous formulations tested in vivo and hopefully may advance to clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was supported by the Consejo Nacional de Ciencia y Tecnología.