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.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Orlistat manifests antitumor and chemosensitizing action implicating modulated regulation of cell survival, reconstituted-tumor microenvironment and altered MDR phenotype.


CONCLUSIONS
These observations indicate that orlistat could be utilized as an adjunct regimen for improving antitumor efficacy of cisplatin.
School of Biotechnology, Banaras Hindu University, Varanasi 221005, India.
Shiva
S
Kant
Ajay
A
Kumar
Sukh Mahendra
SM
Singh
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D007783:Lactones / Q000494:pharmacology*; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D000077403:Orlistat; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000187:drug effects*
D019440:Anti-Obesity Agents; D000970:Antineoplastic Agents; D007783:Lactones; D009573:Nitrites; D012333:RNA, Messenger; D000077403:Orlistat; D052247:Nitric Oxide Synthase Type II; D064429:Fatty Acid Synthases; D002945:Cisplatin
Apoptosis; Chemosensitization; DCFDA; DL; Dalton's lymphoma; FASN; Fatty acid synthase; MDR; MRP-1; NO; Orlistat; ROS; T cell lymphoma; dichlorodihydrofluorescein diacetate; fatty acid synthase; iNOS; inducible nitric oxide synthase; multidrug resistant associated protein-1; multidrug resistant protein; nitric oxide; reactive oxygen species