Mono-PEGylated Thermostable Bacillus caldovelox Arginase Mutant (BCA-M-PEG20) Induces Apoptosis, Autophagy, Cell Cycle Arrest and Growth Inhibition on Gastric Cancer Cells

Abstract

Gastric cancer is one of the most common malignant solid tumors in the world, especially in Asia with high mortality due to a lack of effective treatment. With our newly constructed arginine-depleting enzyme - mono-PEGlyated Bacillus caldovelox arginase mutant (BCA-M-PEG20) drug against multiple cancer cell lines such as cervical and lung cancers, we have explored the potential usage of BCA-M-PEG20 for the treatment of gastric cancer. Our results indicated that BCA-M-PEG20 significantly inhibited argininosuccinate synthetase (ASS) positive gastric cancer cells, MKN-45 and BGC-823, while another arginine-depleting enzyme - arginine deiminase (ADI, currently under Phase III clinical trial), failed to suppress the growth of gastric cancer cells. In vitro studies demonstrated that our BCA-M-PEG20 inhibited MKN-45 cells by inducing autophagy and cell cycle arrest at the S phase under 0.58 U/mL (IC50 values). Significant caspase-dependent apoptosis was induced in MKN-45 after the treatment of 1.16–2.32 U/mL of BCA-M-PEG20. Our in vivo studies showed that administrations of BCA-M-PEG20 with 250 U/mouse twice per week significantly suppressed about 50% of tumor growth in the MKN-45 gastric cancer xenograft model. Taken together, BCA-M-PEG20 demonstrates a superior potential to be an anti-gastric cancer drug.