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S. Xu
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-029 - In Vitro Effects of Pegylated Arginase in Small Cell Lung Cancer (ID 4163)
14:30 - 14:30 | Author(s): S. Xu
- Abstract
Background:
Small cell lung cancer (SCLC) accounts for 15% of all lung cancer cases. SCLC is notoriously difficult to treat with high relapse rate and the current standard treatment remains chemotherapy. Arginine is an important amino acid in normal human cells that can be replenished through urea cycle, but some tumors are arginine-auxotrophic due to deficient argininosuccinate synthetase (ASS1) and/or ornithine transcarbamylase (OTC). BCT-100 is a pegylated arginase, which converts arginine to citrulline, has demonstrated anticancer activity in human melanoma, hepatocellular carcinoma and acute myeloid leukemia. We aim to determine the in vitro effects of BCT-100 in SCLC.
Methods:
A panel of 7 SCLC cell lines was obtained from ATCC. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and protein expression by Western blot. Knockdown of OTC was performed using siRNA. Flow cytometry was applied to detect mitochondrial membrane depolarization (MMD).
Results:
The IC~50~ values of BCT-100 in H69, DMS79, H187, H209, H526, H841 and SW1271 cells were 462.9±112.2, >1000, 24.9±6.4, 8.6±0.8, 10.1±0.7, >1000 and 49.2±7.4 mU/mL respectively. Overexpression of ASS1 in H69 and DMS79 cells, and OTC in H841 cells were associated with resistance to BCT-100. Knocking down of OTC increased sensitivity of BCT-100 in H841 cells partially via apoptosis. H526 cells (BCT-100-sensitive) was selected for mechanistic study. MMD was observed in BCT-100 treatment accompanied by cytochrome c and SMAC release from mitochondria to cytosol. N-acetylcysteine (NAC) could significantly reverse apoptosis induced by BCT-100. Besides, cyclin A2, cyclin B1 and CDK7 were downregulated in a time-dependent manner. The protein expression of p-AKT and p-mTOR was increased after exposure while RAS/RAF/ERK cell signaling pathway was inhibited with BCT-100 treatment.
Conclusion:
SCLC cell lines with low ASS1 and OTC expression were sensitive to arginine depletion with BCT-100, mediated through oxidative stress, cell cycle arrest and apoptotic pathway.
