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 |
| |
Authors: | Shiva Kant Ajay KumarSukh Mahendra Singh |
| |
Affiliation: | School of Biotechnology, Banaras Hindu University, Varanasi 221005, India |
| |
Abstract: | BackgroundOrlistat, 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.MethodsTumor-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.ResultsOrlistat 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.ConclusionOrlistat manifests antitumor and chemosensitizing action implicating modulated regulation of cell survival, reconstituted-tumor microenvironment and altered MDR phenotype.General significanceThese observations indicate that orlistat could be utilized as an adjunct regimen for improving antitumor efficacy of cisplatin. |
| |
Keywords: | DCFDA, dichlorodihydrofluorescein diacetate DL, Dalton's lymphoma FASN, fatty acid synthase iNOS, inducible nitric oxide synthase MRP-1, multidrug resistant associated protein-1 MDR, multidrug resistant protein NO, nitric oxide ROS, reactive oxygen species |
本文献已被 ScienceDirect 等数据库收录! |
|