Stearoyl-CoA-Desaturase Inhibition Significantly Reduces the Growth of Pancreatic Cancer
Aims: To determine the potency of Stearoyl-CoA-Desaturase 1 (SCD1) inhibition as a viable treatment option or chemotherapy supplementation for patients with Pancreatic Cancer and how it affects tumour-derived microparticle production. Method: PANC-1 cells were incubated with CAY10566 (0.125-2M), an inhibitor of SCD1 for 120hours. These were then counted, assayed for viability and the presence of Tissue Factor (CD142) and Basigin (CD147) was determined using flow cytometry. The migration of treated cells through a basement membrane was determined using Matrigel in a transwell invasion assay. The viability of cells treated with SCDi, Gemcitabine chemotherapy and both drugs in combination was assessed by MTT assay both immediately after incubation and after 48 hours recovery in complete medium to determine reversibility. Cells were also prepared and imaged using scanning electron microscopy (SEM) to observe any morphological changes induced by the treatments. Results: When stained for viability, no significant induction of apoptosis or necrosis by either drug was observed. When determined by MTT assay the IC50 values for SCDi and Gemcitabine were 142.4 and 13.05nm respectively. Cellular growth after recovery in complete medium (to mimic periods between treatment) was significantly lower after treatment with SCDi alone compared to SCDi in combination with Gemcitabine (38%2.19 SCDi v 153%9.45 SCDi+Gem)(P<0.05). SCDi treatment reduces the migration of CD147+ cells compared to both the vehicle control and Gemcitabine treatment (55.8% SCDi v 61% CON v 58% Gem). SEM imaging revealed that SCDi treated cells have a much flatter phenotype than vehicle control cells, and those treated with Gemcitabine and SCDi in combination are sparser, swollen in size (174m CON v 552m SCDi+Gem) and have a very flat phenotype. Conclusion: Both SCDi and Gemcitabine treatment affect the microscopic and flow cytometric phenotype of PANC1 cells. SCD1 inhibition is a promising treatment option for PC patients with a low IC50 value indicating high potency and a synergistic mechanism observed when used in combination with Gemcitabine. This indicates that treatment may be a suitable supplementation for standard therapy. Further work is required to elucidate the mechanism of growth inhibition induced by SCDi.
Citation : Hackney, A.B., Chung, W.Y., Dennison, A.R., Martin, N. (2018) Stearoyl-CoA-Desaturase Inhibition Significantly Reduces the Growth of Pancreatic Cancer.Pancreatic Society of Great Britain and Ireland Annual General Meeting, Leicester, November 2018