orlistat and Colonic-Neoplasms

Colon cancer is a highly anabolic entity with upregulation of glycolysis, glutaminolysis, and de novo synthesis of fatty acids, which also induces a hypercatabolic state in the patient. The blockade of either cancer anabolism or host catabolism has been previously proven to be a successful anticancer experimental treatment. However, it is still unclear whether the simultaneous blockade of both metabolic counterparts can limit malignant survival and the energetic consequences of such an approach. In this chapter, by using the CT26.WT murine colon adenocarcinoma cell line as a model of study, we provide a method to simultaneously perform a pharmacological blockade of tumor anabolism and host catabolism, as a feasible therapeutic approach to treat cancer, and to limit its energetic supply.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colonic Neoplasms; Diazooxonorleucine; Drug Screening Assays, Antitumor; Fatty Acid Synthase, Type I; Fatty Acids; Female; Glutaminase; Glutamine; Glycolysis; Hexokinase; Indazoles; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Orlistat; Smegmamorpha

The malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Daunorubicin; Energy Metabolism; Gene Expression Regulation, Neoplastic; Glycolysis; Growth Hormone; Humans; Indazoles; Indomethacin; Insulin; Metabolic Networks and Pathways; Metabolism; Mice; Mitoxantrone; Orlistat; Oxidative Phosphorylation; Vincristine

Topics: Aged; Anti-Obesity Agents; Carcinoembryonic Antigen; Colonic Neoplasms; Female; Humans; Lactones; Lung Neoplasms; Orlistat; Solitary Pulmonary Nodule

Orlistat is an anti-obesity agent that increases the fecal fat excretion, which promotes colon carcinogenesis. Therefore, the present study was designed to verify the effects of Orlistat on the formation of rat colonic aberrant crypt foci (ACF) and cell proliferation evaluated by the PCNA method. Male Wistar rats received either a standard diet or a high fat diet (HFD), supplemented or not with Orlistat (200mg/kg chow) and two doses of the carcinogen dimethyl-hydrazine (25mg/Kg). After 30 days, Orlistat was associated to a significant increase in the number of colonic ACFs and cell proliferation in DMH-treated animals, independently of the HFD.

Topics: 1,2-Dimethylhydrazine; Animals; Anti-Obesity Agents; Carcinogens; Cell Proliferation; Colonic Neoplasms; Intestinal Mucosa; Lactones; Lipase; Male; Orlistat; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar