The effect of FASN inhibition on the growth and metabolism of a cisplatin‐resistant ovarian carcinoma model |
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Authors: | Efthymia Papaevangelou Gilberto S. Almeida Carol Box Nandita M. deSouza Yuen‐Li Chung |
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Affiliation: | 1. Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom;2. Department of Surgery and Cancer, Faculty of Medicine, Imperial Centre for Translational & Experimental Medicine (ICTEM), Imperial College London, Hammersmith Hospital Campus, London, United Kingdom |
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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. |
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Keywords: | FASN orlistat ovarian cancer cisplatin resistance metabolism MRS |
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