Co-treatment With A C1B5 Peptide Of Protein Kinase Cγ ... - PubMed

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Abstract

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.

Keywords: Apoptosis; C1B domain peptides; C1B5 peptide; Pancreatic cancer; Protein kinase Cγ (PKCγ); T cell activation.

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Conflict of interest statement

Disclosure of potential conflicts of interest: No potential conflicts of interest were disclosed.

Figures

Figure 1

Figure 1

Co-treatment with C1B5 peptide and…

Figure 1

Co-treatment with C1B5 peptide and gemcitabine decreased the growth of PAN02 murine and…

Figure 1 Co-treatment with C1B5 peptide and gemcitabine decreased the growth of PAN02 murine and PANC-1 human pancreatic carcinoma cells in both 2D cell and 3D spheroid cultures. (A), The attenuating effects of C1B5 peptide, gemcitabine (Gem), and the co-treatment in 2D cultures were evaluated at 48 hrs after treatment by MTT assay (n = 3). (B), Typical image of PAN02 spheroid in each group. (C), The attenuating effects of C1B5 peptide, gemcitabine, and the co-treatment in PAN02 and PANC-1 spheroid cultures were evaluated at Day 9 (PAN02) and Day 12 (PANC-1) after the initiation of spheroid culture (n = 5). *, P<0.05.
Figure 2

Figure 2

Co-treatment with C1B5 peptide and…

Figure 2

Co-treatment with C1B5 peptide and gemcitabine significantly decreased the growth of pancreatic tumors…

Figure 2 Co-treatment with C1B5 peptide and gemcitabine significantly decreased the growth of pancreatic tumors in mouse peritoneal cavity. (A), Average tumor weight in mesentery in PBS control, 15 mg/kg gemcitabine (Gem) alone, 20 mg/kg C1B5 peptide alone, and the combination group (n = 4-5). (B), Typical image of H & E stained tumor tissues in PBS control (a), gemcitabine alone (b), C1B5 peptide alone (c), and co-treatment with C1B5 and gemcitabine (d). 40× magnification. (C-D), The number of tumor nodules (C) and its relative tumor area (D) in 5 randomly selected areas in H & E stained samples (n = 4-5). (E-F), The evaluation of apoptosis-induced cells in tumors (n = 4-5) by TUNEL (E) and the cleaved caspase-3 (F). a-c, P

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