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.
Highlights
Sustained myelopoiesis considered essential to overcome myelosupression in tumor-bearing hosts associated with tumor progression and chemotherapeutic applications [1,2,3]
Further to investigate if the observed augmentation of bone marrow cellularity is associated with an altered cell survival, bone marrow cells (BMC) (1x106 cells/ml) harvested from control and orlistat-administered tumor-bearing hosts were cultured for 24 h in 96 well culture plates followed by MTT assay for estimating cell survival (Figure 2c) or processed for enumeration of apoptotic population by Wright Giemsa staining (Figure 2d) and TUNEL assays (Figure 2e)
In view of the observations indicating that orlistat augmented macrophage differentiation, we examined if orlistat administration modulated the number of F4/80+ tumor-associated macrophages (TAM)
Summary
Sustained myelopoiesis considered essential to overcome myelosupression in tumor-bearing hosts associated with tumor progression and chemotherapeutic applications [1,2,3]. Fatty acid synthase (FASN)-dependent de novo fatty acid synthesis is identified as an indispensable necessity of hematopoiesis, differentiation and activation of macrophages (Mφ), which play a central role in host’s antitumor defense [4,5,6,7,8,9]. Reports indicate that FASN inhibition arrests membrane-associated functions of macrophages and their differentiation from monocytes [7]. To the best of our knowledge there is no report regarding the action of orlistat on myelopoietic differentiation of macrophages in tumor-bearing hosts.
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