In Vivo Effectiveness of Orlistat in the Suppression of Human Colorectal Cancer Cell Proliferation

Abstract

Background/Aim: Fatty acid synthase (FASN) provides palmitate for cell membrane formation in colorectal cancer (CRC) cells, however, palmitate is also available in the blood of CRC patients. The aim of this study was to examine whether orlistat, a FASN inhibitor, is able to attenuate CRC cell growth despite the availability of extracellular palmitate. Materials and Methods: Palmitate concentrations were measured in serum from CRC patients and healthy controls. HT-29 CRC cells were treated with orlistat and palmitate. Results: Treatment of CRC cells with orlistat caused a dose-dependent inhibition of cell proliferation. In turn, delivery of extracellular palmitate at doses lower than those found in the serum of CRC patients reversed inhibition by orlistat concentrations of up to 10 μM. Conclusion: Inhibition of CRC cell proliferation by orlistat is reversed by palmitate which is present at high levels in the serum. Therefore, orlistat may be effective in vivo only at high concentrations.Colorectal cancer (CRC) is one of the leading causes of mortality among cancer patients, and the search for new therapies is still underway. Due to advances in screening techniques and improvements in treatments, the death rate from colorectal cancer has been decreasing in the United States and Europe. However, a trend of increasing incidence of the disease has been observed in recently developed countries (1). This cancer tends to affect men and women equally, but men tend to develop it at a younger age (2). CRC can often be sporadic; however, hereditary forms are also common in this entity (2). Recent evidence shows that CRC is associated with considerable changes in lipid composition and metabolism in cancer cells (3, 4). One of the alterations characteristic of many cancers is enhanced lipogenesis, a process that provides lipids for cell membrane formation in rapidly proliferating cancer cells (5). Some authors have reported overexpression of fatty acid synthase (FASN), the major enzyme which produces palmitic acid, in CRC tissue (6-8). Furthermore, FASN levels in the serum of colorectal cancer patients are significantly higher than that in healthy individuals; thus, this enzyme may be a potential tumor marker (9). FASN knockdown has been associated with the inhibition of CRC cell proliferation (10). Moreover, FASN expression increases with tumor progression in certain tumor types, including colorectal cancer and is associated with increased disease aggressiveness and diminished survival and response to classical chemotherapeutic agents (11)(12)(13). Thus, research on inhibitors of FASN as potential anticancer therapies is underway (5). Orlistat (tetrahydrolipstatin) is a drug used for the treatment of obesity. Orlistat is an inhibitor of pancreatic and gastric lipase, and its action leads to decreased absorption of dietary fat (14). This agent, which is administered by the oral route, is minimally absorbed by the gastrointestinal tract and reduces the lipid supply from outside sources. However, orlistat is also an inhibitor...

Fatty acid synthase inhibitor orlistat impairs cell growth and down-regulates PD-L1 expression of a human T-cell leukemia line

“…The anti-proliferative effect of orlistat appears to be associated with FASN inhibition as it was partially reverted by co-treatment of Jurkat cells with SP, the final product of FASN activity. This aspect is of clinical relevance as recently shown by Czumaj et al 46 since SP can be present at high levels in the serum of colon cancer patients, leading to the requirement of higher doses of orlistat for possible therapeutic success. We found also that, beside the inhibition of the enzymatic activity, orlistat is able to reduce FASN protein levels.…”

Decreased Triacylglycerol Content and Elevated Contents of Cell Membrane Lipids in Colorectal Cancer Tissue: A Lipidomic Study

“…Most authors reported overexpression of lipogenic enzymes in cancer tissues or cells [17]. The overexpression of enzymes from this group, specifically FASN [40] and SCD1 [41] involved in the synthesis of oleic acid, the main component of triglycerides, was also found in CRC. These findings imply that the contents of lipids, including triglycerides, in cancer tissues should be elevated.…”

Preferential uptake of polyunsaturated fatty acids by colorectal cancer cells

“…None of the patients received preoperative neoadjuvant treatment and omega-3 FA supplementation. The tissue and serum sample collection was performed as we described previously 3,8 . The tissue samples were collected from both the tumor and normal large intestinal mucosa, at least 5 cm from the tumor interface.…”

“…Fatty acids (FAs) are a heterogeneous group of lipids with different chain length, degree of saturation and metabolic effects 2 . A growing body of evidence shows that CRC is associated with alterations of FA profiles in serum and tumor tissues [3][4][5][6][7][8] . Recently, we demonstrated an increase in the levels of saturated and monounsaturated very long chain FAs in tumor tissues and sera of CRC patients 3 , co-existing with enhanced expression of FA elongases 1 and 6 in cancer tissues 3 .…”