The effect of FASN inhibition on the growth and metabolism of a cisplatin-resistant ovarian carcinoma model.
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ICR Authors
Authors
Papaevangelou, E
Almeida, GS
Box, C
deSouza, NM
Chung, Y-L
Almeida, GS
Box, C
deSouza, NM
Chung, Y-L
Document Type
Journal Article
Date
2018-08-15
Date Accepted
2018-02-28
Abstract
Overexpression of fatty acid synthase (FASN), a key regulator of the de novo synthesis of fatty acids, has been demonstrated in a variety of cancers and is associated with poor prognosis and increased multidrug resistance. Inhibition of FASN with the anti-obesity drug orlistat has been shown to have significant anti-tumourigenic effects in many cancers, notably breast and prostate. In our study, we investigated whether FASN inhibition using orlistat is an effective adjunctive treatment for ovarian cancers that have become platinum resistant using a cisplatin-resistant ovarian tumour xenograft model in mice. Mice were treated with orlistat or cisplatin or a combination and metabolite analysis and histopathology were performed on the tumours ex vivo. Orlistat decreased tumour fatty acid metabolism by inhibiting FASN, cisplatin reduced fatty acid β-oxidation, and combination treatment delayed tumour growth and induced apoptotic and necrotic cell death in cisplatin-resistant ovarian cancer cells over and above that with either treatment alone. Combination treatment also decreased glutamine metabolism, nucleotide and glutathione biosynthesis and fatty acid β-oxidation. Our data suggest that orlistat chemosensitised platinum-resistant ovarian cancer to treatment with platinum and resulted in enhanced efficacy.
Citation
International journal of cancer, 2018, 143 (4), pp. 992 - 1002
Source Title
Publisher
WILEY
ISSN
0020-7136
eISSN
1097-0215
Collections
Research Team
Magnetic Resonance
Radiotherapy Physics Modelling
Radiotherapy Physics Modelling