title: Myelopoietic efficacy of orlistat in murine hosts bearing T cell lymphoma: implication in macrophage differentiation and activation.
abstract: Orlistat, an inhibitor of fatty acid synthase (FASN), acts as an antitumor agent by blocking de novo fatty acid synthesis of tumor cells. Although, myelopoiesis also depends on de novo fatty acid synthesis, the effect of orlistat on differentiation of macrophages, which play a central role in host's antitumor defence, remains unexplored in a tumor-bearing host. Therefore, the present investigation was undertaken to examine the effect of orlistat administration on macrophage differentiation in a T cell lymphoma bearing host. Administration of orlistat (240 mg/kg/day/mice) to tumor-bearing mice resulted in a decline of tumor load accompanied by an augmentation of bone marrow cellularity and survival of bone marrow cells (BMC). The expression of apoptosis regulatory caspase-3, Bax and Bcl2 was modulated in the BMC of orlistat-administered tumor-bearing mice. Orlistat administration also resulted in an increase in serum level of IFN-γ along with decreased TGF-β and IL-10. BMC of orlistat-administered tumor-bearing mice showed augmented differentiation into macrophages accompanied by enhanced expression of macrophage colony stimulating factor (M-CSF) and its receptor (M-CSFR). The macrophages differentiated from BMC of orlistat-administered mice showed characteristic features of M1 macrophage phenotype confirmed by expression of CD11c, TLR-2, generation of reactive oxygen species, phagocytosis, tumor cell cytotoxicity, production of IL-1,TNF-α and nitric oxide. These novel findings indicate that orlistat could be useful to support myelopoesis in a tumor-bearing host.
authors.affiliation: School of Biotechnology, Banaras Hindu University, Varanasi, India.
authors.forename: Shiva
authors.initials: S
authors.lastname: Kant
authors.affiliation: School of Biotechnology, Banaras Hindu University, Varanasi, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.affiliation: School of Biotechnology, Banaras Hindu University, Varanasi, India.
authors.forename: Sukh Mahendra
authors.initials: SM
authors.lastname: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology; D016399:Lymphoma, T-Cell / Q000473:pathology*; D008262:Macrophage Activation / Q000187:drug effects*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D038042:Myelopoiesis / Q000187:drug effects*; D000077403:Orlistat; D010641:Phenotype; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism
chemical_list: D007783:Lactones; D016173:Macrophage Colony-Stimulating Factor; D000077403:Orlistat; D016186:Receptor, Macrophage Colony-Stimulating Factor