The anti-obesity agent Orlistat is associated to increase in colonic preneoplastic markers in rats treated with a chemical carcinogen

Garcia, Sérgio Britto; Barros, Luane Taísa da Costa; Turatti, Aline; Martinello, Flávia; Modiano, Patrícia; Ribeiro‐Silva, Alfredo; Vespúcio, Marcelo Vinícius de Oliveira; Uyemura, Sérgio Akira

doi:10.1016/j.canlet.2005.09.011

Cited by 47 publications

(27 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Currently, there are 3 obesity drugs commonly prescribed. Xenical (orlistat) is a gastrointestinal lipase inhibitor known to cause moderate weight loss, but is associated with adverse gastrointestinal effects including colon cancer (3). Sibutramine, a monoamine reuptake inhibitor, results in greater weight loss compared with orlistat, but is associated with increased blood pressure and elevated heart rate.…”

mentioning

confidence: 99%

gp130 receptor ligands as potential therapeutic targets for obesity

Febbraio

2007

J. Clin. Invest.

109

View full text Add to dashboard Cite

Obesity and its related cluster of pathophysiologic conditions including insulin resistance, glucose intolerance, dyslipidemia, and hypertension are recognized as growing threats to world health. It is now estimated that 10% of the world's population is overweight or obese. As a result, new therapeutic options for the treatment of obesity are clearly warranted. Recent research has focused on the role that gp130 receptor ligands may play as potential therapeutic targets in obesity. One cytokine in particular, ciliary neurotrophic factor (CNTF), acts both centrally and peripherally and mimics the biologic actions of the appetite control hormone leptin, but unlike leptin, CNTF appears to be effective in obesity and as such may have therapeutic potential. In addition, CNTF suppresses inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. This review examines the potential role of gp130 receptor ligands as part of a therapeutic strategy to treat obesity.Nonstandard abbreviations used: ACC, acetyl-CoA carboxylase; AMPK, AMP kinase; CNTF, ciliary neurotrophic factor; CNTFRa, CNTF receptor a; gp130R, gp130 receptor; IL-6R, IL-6 receptor; LIF, leukemia inhibitory factor; LIFRb, LIF receptor b; LRb, long form of the leptin receptor; PGC-1a, PPARg coactivator 1a; POMC, proopiomelanocortin; SHP-2, Src homology-containing tyrosine phoshatase 2. Conflict of interest:The author has declared that no conflict of interest exists.Citation for this article:

show abstract

mentioning

confidence: 99%

gp130 receptor ligands as potential therapeutic targets for obesity

Febbraio

2007

J. Clin. Invest.

109

View full text Add to dashboard Cite

show abstract

“…The possibility that orlistat could be directly involved in colorectal carcinogenesis has been matter of debate for several years (9,10,41). However, no conclusive results have been obtained so far, although the finding that orlistat did not show carcinogenic potential (41) does not support the hypothesis that the agent is carcinogenic per se.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, orlistat has been found to augment pro-apoptotic NOXA protein (8), thus reinforcing its possible cancer protective activity. However, preclinical studies performed on rats exposed to predisposing factors for colon cancer (i.e., receiving high fat diet alone or combined with the carcinogen compound methyl hydrazine), showed that long-term treatment with orlistat lead to severe crypt alterations of colonic mucosa, that are considered colon cancer biomarkers (9,10).…”

Section: Introductionmentioning

confidence: 99%

Influence of fatty acid synthase inhibitor orlistat on the DNA repair enzyme O6-methylguanine-DNA methyltransferase in human normal or malignant cells in vitro

Cioccoloni

Bonmassar

Pagani

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. Tetrahydrolipstatin (orlistat), an inhibitor of lipases and fatty acid synthase, is used orally for long-term treatment of obesity. Although the drug possesses striking antitumor activities in vitro against human cancer cells and in vitro and in vivo against animal tumors, it also induces precancerous lesions in rat colon. Therefore, we tested the in vitro effect of orlistat on the expression of O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme that plays an essential role in the control of mutagenesis and carcinogenesis. Western blot analysis demonstrated that 2-day continuous exposure to 40 µM orlistat did not affect MGMT levels in a human melanoma cell line, but downregulated the repair protein by 30-70% in human peripheral blood mononuclear cells, in two leukemia and two colon cancer cell lines. On the other hand, orlistat did not alter noticeably MGMT mRNA expression. Differently from lomeguatrib (a false substrate, strong inhibitor of MGMT) orlistat did not reduce substantially MGMT function after 2-h exposure of target cells to the agent, suggesting that this drug is not a competitive inhibitor of the repair protein. Combined treatment with orlistat and lomeguatrib showed additive reduction of MGMT levels. More importantly, orlistat-mediated downregulation of MGMT protein expression was markedly amplified when the drug was combined with a DNA methylating agent endowed with carcinogenic properties such as temozolomide. In conclusion, even if orlistat is scarcely absorbed by oral route, it is possible that this drug could reduce local MGMT-mediated protection against DNA damage provoked by DNA methylating compounds on gastrointestinal tract epithelial cells, thus favoring chemical carcinogenesis.

show abstract

“…Among the initial modifications causing the CRC onset, there is the suppression of the serotonergic system that seems to be related to a high-fat diet [76]. Moreover, this type of diet enhances the formation of preneoplastic lesions and consequently promotes CRC tumorigenesis [77]. However, it has been shown that, during the advanced stages, the disease can induce a reduction of serum total cholesterol levels [78].…”

Section: Colorectal Cancermentioning

confidence: 99%

Dietary restriction: could it be considered as speed bump on tumor progression road?

et al. 2016

View full text Add to dashboard Cite

Dietary restrictions, including fasting (or long-term starvation), calorie restriction (CR), and short-term starvation (STS), are considered a strong rationale that may protect against various diseases, including age-related diseases and cancer. Among dietary approaches, STS, in which food is not consumed during designed fasting periods but is typically not restricted during designated feeding periods, seems to be more suitable, because other dietary regimens involving prolonged fasting periods could worsen the health conditions of cancer patients, being they already naturally prone to weight loss. Until now, the limited amount of available data does not point to a single gene, pathway, or molecular mechanism underlying the benefits to the different dietary approaches. It is well known that the healthy effect is mediated in part by the reduction of nutrient-related pathways. The calorie restriction and starvation (long-and short-term) also suppress the inflammatory response reducing the expression, for example, of IL-10 and TNF-α, mitigating pro-inflammatory gene expression and increasing anti-inflammatory gene expression. The dietary restriction may regulate both genes involved in cellular proliferation and factors associated to apoptosis in normal and cancer cells. Finally, dietary restriction is an important tool that may influence the response to chemotherapy in preclinical models.However, further data are needed to correlate dietary approaches with chemotherapeutic treatments in human models. The aim of this review is to discuss the effects of various dietary approaches on the cancer progression and therapy response, mainly in preclinical models, describing some signaling pathways involved in these processes.

show abstract

The anti-obesity agent Orlistat is associated to increase in colonic preneoplastic markers in rats treated with a chemical carcinogen

Cited by 47 publications

References 20 publications

gp130 receptor ligands as potential therapeutic targets for obesity

gp130 receptor ligands as potential therapeutic targets for obesity

Influence of fatty acid synthase inhibitor orlistat on the DNA repair enzyme O6-methylguanine-DNA methyltransferase in human normal or malignant cells in vitro

Dietary restriction: could it be considered as speed bump on tumor progression road?

Contact Info

Product

Resources

About