A preclinical study of the combined treatment of arginase and canavanine in pancreatic cancer
Refereed conference paper presented and published in conference proceedings

摘要Background: Arginine deprivation by arginase is a novel approach for cancer treatment as some cancers were found to be arginine auxotrophic. PEG-BCT-100, a pegylated form of recombinant human arginase, was used to investigate the effect of arginine deprivation on pancreatic cell lines. Canavanine (CAV) is a natural toxic analog of arginine isolated from leguminous plant which shares similar structure to L-arginine. The cytotoxicity of CAV has been shown by replacing arginine into newly synthesized proteins during translation. Consequently, the protein function and critical metabolism for cancer cell growth may be disrupted. In this study, we have also tested the efficacy of combined arginase and CAV treatment on pancreatic cell lines.

Methods: Pancreatic cell lines MIA PaCa-2, CFPAC-1 and normal lung fibroblast cell line WI-38, were either incubated in normal or arginine free condition. The corresponding IC50 of CAV was determined by cell viability assay. To evaluate the responsiveness to the combined treatment, cells were monitored by live cell imaging under the conditions of PEG-BCT-100 treatment alone (0.3IU/ml) or in combination with CAV (10μM or 50μM). The apoptotic effect of the combined treatment was examined by Western blotting and Annexin V assay.

Results: Either arginase or CAV treatment could inhibit pancreatic cancer cell growth. The cells treated with CAV in arginine free condition demonstrated significant inhibition of cell proliferation and its corresponding IC50 was significantly lowered from millimolar to micromolar when arginine was withdrawn. Strong synergism of CAV and PEG-BCT-100 was observed after 48-hour treatment with enhanced apoptosis in pancreatic cell lines, but not in normal lung fibroblast cells. Both early and late apoptosis were observed in co-treated pancreatic cancer cells as indicated by Annexin V assay and the detection of polyADP ribosyl polymerase (PARP) in Western blot.

Conclusion: Arginine deprivation by PEG-BCT-100 combined with CAV shows strong synergetic effect on inducing cell death in pancreatic cell lines, suggesting that the supplement of CAV could facilitate the treatment outcome of arginine deprivation by arginase. This combined treatment may serve as a treatment strategy for pancreatic cancer.
著者TT Kwong, CH Wong, HH Loong, Stephen L Chan
會議名稱American Association for Cancer Research (AACR) Annual Meeting 2017
會議地點Washington, D.C.
會議論文集題名Proceedings of the American Association for Cancer Research AACR Annual Meeting 2017
關鍵詞Pancreatic cancer, Arginine deprivation, PEG-BCT-100, Canavanine

上次更新時間 2018-22-01 於 05:54