Tumor growth retardation and chemosensitizing action of fatty acid synthase inhibitor orlistat on T cell lymphoma: Implication of reconstituted tumor microenvironment and multidrug resistance phenotype

• Published in: Biochimica et biophysica acta Vol. 1840; no. 1; pp. 294 - 302
• Main Authors: Kant, Shiva, Kumar, Ajay, Singh, Sukh Mahendra
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2014
• Subjects: acidosis; adenosinetriphosphatase; Animals; Anti-Obesity Agents - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Blotting, Western; caspase-3; Cell Proliferation - drug effects; cell viability; Chemosensitization; cisplatin; Cisplatin - pharmacology; cytokines; Disease Models, Animal; Drug Resistance, Multiple - drug effects; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Fatty acid synthase; Fatty Acid Synthases - antagonists & inhibitors; Fatty Acid Synthases - genetics; Fatty Acid Synthases - metabolism; Flow Cytometry; gene expression; growth retardation; Lactones - pharmacology; longevity; Lymphoma, T-Cell - metabolism; Lymphoma, T-Cell - pathology; Lymphoma, T-Cell - prevention & control; Mice; Mice, Inbred BALB C; multiple drug resistance; neoplasm cells; nitric oxide; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitrites - metabolism; Orlistat; phenotype; proteins; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; staining; T cell lymphoma; T-lymphocytes; Tumor Microenvironment - drug effects; Western blotting; NO; DL; MRP-1; Chemosensitization; FASN; T cell lymphoma; ROS; Orlistat; DCFDA; iNOS; MDR; Fatty acid synthase; Apoptosis; nitric oxide; multidrug resistant associated protein-1; inducible nitric oxide synthase; dichlorodihydrofluorescein diacetate; Dalton's lymphoma; reactive oxygen species; multidrug resistant protein
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.09.020

Orlistat, a fatty acid synthase (FASN) inhibitor, has been demonstrated to inhibit tumor cell survival. However, the mechanism(s) of its tumor growth retarding action against malignancies of hematological origin remains unclear. It is also not understood if the antitumor action of orlistat implicates modulated susceptibility of tumor cell to anticancer drugs. Therefore, the present investigation focuses to study the antitumor and chemosensitizing action of orlistat in a murine host bearing a progressively growing T cell lymphoma. Tumor-bearing mice were administered with vehicle alone or containing orlistat followed by administration of PBS with or without cisplatin. Tumor progression and survival of tumor-bearing host were monitored along with analysis of tumor cell survival and apoptosis. Tumor ascitic fluid was examined for pH, NO and cytokines. Expression of genes and proteins was investigated by RT-PCR and western blot respectively. ROS was analyzed by DCFDA staining and FASN activity by spectrophotometry. Orlistat administration to tumor-bearing mice resulted in tumor growth retardation, prolonged life span, declined tumor cell survival and chemosensitization to cisplatin. It was accompanied by increased osmotic fragility, modulated acidosis, expression of ROS, NO, cytokines, MCT-1 and VH+ ATPase, Bcl2, Caspase-3, P53, inhibited FASN activity and declined expression of MDR and MRP-1 proteins. Orlistat manifests antitumor and chemosensitizing action implicating modulated regulation of cell survival, reconstituted-tumor microenvironment and altered MDR phenotype. These observations indicate that orlistat could be utilized as an adjunct regimen for improving antitumor efficacy of cisplatin. •Orlistat exerts antitumor and chemosensitizing action.•Orlistat alters cell survival regulation, pH homeostasis and MDR phenotype.•Orlistat reconstitutes tumor microenvironment.