PWE-018 HSPC1 Inhibitors Potentiate the Effect of 5-FU in Primary Colorectal Cancer Cell Model


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Abstract

IntroductionColorectal cancer (CRC) is the fourth most common cancer in the UK and was responsible for more than 15,000 deaths in 2011.1 Less than 50% of patients with Dukes stage C and D survive more than 5 years.2Molecular chaperone Heat shock protein (HSP) C1 is elevated in CRC.3 HSPC1’s client proteins (e.g., HER2, pNF-ĸB, Akt etc.) are involved in key cellular pathways and apoptosis. HSPC1 inhibitors recently showed positive clinical results in breast cancer4 and non-small cell lung carcinoma.5 This study aims to explore the effect of combining HSPC1 inhibitors with 5-fluorouracil (5-FU), the mainstay chemotherapy, in CRC.MethodsCRC cell line HT29 were treated with HSPC1 inhibitors 17-DMAG and NVP-AUY922 as single agent and in combination with 5-FU.Six primary CRC samples were obtained immediately following surgical resection with consent and treated with HSPC1 inhibitors. Four subsequent samples were treated with a combination of HSPC1 inhibitors and 5-FU.Following treatment, cell metabolism rate and apoptosis were assessed using MTS and caspase-3 assay.ResultsIn HT29, 17-DMAG was effective in inducing apoptosis and reducing cell proliferation whereas NVP-AUY922 did not. When combined with 5-FU, 17-DMAG showed additive effect.In primary CRC cells, a 50% reduction in cell metabolism rate was observed in 2/6 samples for 17-DMAG and 1/5 samples for NVP-AUY922. When subsequent primary samples were treated with 5-FU and HSPC1 inhibitors, significant decrease in cell metabolism rate and increase in apoptosis were observed in 1/4 samples.ConclusionHSPC1 inhibitors are able to potentiate the chemotherapeutic effect of 5-FU in CRC cell line and this result may be replicated in primary colorectal cancer cells obtained from surgical specimen. HSPC1 inhibitors have different mode of actions which is evident in the different response observed in both HT29 and primary cells. In addition, CRC cells have individual response to HSPC1 inhibitors and some were not responsive.Although a small sample size, this study encouraged our next phase of research combining HSPC1 inhibitors with current chemotherapeutic agents including oxaliplatin and irinotecan. Further studies will also focus on identifying potential biomarkers to select susceptible patients.ReferencesCancer Research UK, 2013National Cancer Intellidence Network (NCIN), 2009Milicevic, Z, et al. International Journal of Oncology 2008. 32(6):p. 1169–1178Modi, S, et al. Clin Cancer Res 2011;17(15):5132–9Sequist, LV, et al. J Clin Oncol 2010:28(33):4953–60Disclosure of InterestNone Declared.

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