Co-treatment with a C1B5 peptide of protein kinase Cγ and a low dose of gemcitabine strongly attenuated pancreatic cancer growth in mice through T cell activation

• Published in: Biochemical and biophysical research communications 2018-01, Vol.495 (1), p.962-968
• Main Authors: Ishiguro, Susumu, Kawabata, Atsushi, Zulbaran-Rojas, Alejandro, Monson, Kelsey, Uppalapati, Deepthi, Ohta, Naomi, Inui, Makoto, Pappas, Charalampos G., Tzakos, Andreas G., Tamura, Masaaki
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Apoptosis; C1B domain peptides; C1B5 peptide; CELL CULTURES; Cell Line, Tumor; Cell Proliferation - drug effects; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dose-Response Relationship, Drug; Female; Humans; LYMPHOCYTES; MESSENGER-RNA; MICE; Mice, Inbred C57BL; NEUTROPHILS; PANCREAS; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Peptide Fragments - administration & dosage; Peptide Fragments - chemistry; PEPTIDES; Protein Kinase C - administration & dosage; Protein Kinase C - chemistry; Protein kinase Cγ (PKCγ); SIDE EFFECTS; T cell activation; T-Lymphocytes - drug effects
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.11.102

Although gemcitabine is an effective chemotherapeutic for pancreatic cancer, severe side effects often accompany its use. Since we have discovered that locally administered C1B domain peptides effectively control tumor growth without any side effects, the efficacy of co-treatment with this peptide and a low dose of gemcitabine on the growth of pancreatic cancer was examined. Two- and three-dimensional cell culture studies clarified that a co-treatment with C1B5 peptide and gemcitabine significantly attenuated growth of PAN02 mouse and PANC-1 human pancreatic cancer cells in 2D and 3D cultures. Although treatment with the low dose of gemcitabine alone (76%) or the C1B5 peptide alone (39%) inhibited tumor growth moderately, a co-treatment with C1B5 peptide and a low dose of gemcitabine markedly inhibited the growth of PAN02 autografts in the mouse peritoneal cavity (94% inhibition) without any noticeable adverse effect. The number of peritoneal cavity-infiltrating neutrophils and granzyme B+ lymphocytes was significantly higher in the co-treatment group than in the control group. A significant increase of granzyme B mRNA expression was also detected in human T cells by the co-treatment. Taken together, the current study suggests that C1B5 peptide offers a remarkably effective combination treatment strategy to reduce side effects associated with gemcitabine, without losing its tumoricidal effect. •Co-treatment of C1B5 peptide and gemcitabine inhibits pancreatic cancer cell growth in vitro.•Co-treatment of C1B5 peptide and a low dose of gemcitabine attenuates the growth of pancreatic cancer autografts in mice.•Co-treatment of C1B5 peptide and gemcitabine increases neutrophils and granzyme B+ lymphocytes in tumor microenvironment.