In Vivo Adriamycin-induced Apoptosis in Peritoneal Murine Macrophages: Partial Participation of a Caspase Cascade

• Published in: Anticancer research 2004-09, Vol.24 (5A), p.2689-2696
• Main Authors: JORGE R. DOMINGUEZ-RODRIGUEZ, VERONICA CHAPARRO-HUERTA, GEORGINA HERNANDEZ-FLORES, PIEDAD C. GOMEZ-CONTRERAS, JOSÉ M. LERMA-DIAZ, PABLO C. ORTIZ-LAZARENO, RAMON CERVANTES-MUNGUIA, SIMONE ORBACH-ARBOUYS, DANIEL SCOTT-ALGARA, ALEJANDRO BRAVO CUELLAR
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Caspase 9; Caspase Inhibitors; Caspases - metabolism; Doxorubicin - pharmacology; Intracellular Membranes - drug effects; Intracellular Membranes - physiology; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - enzymology; Male; Medical sciences; Membrane Potentials - drug effects; Membrane Potentials - physiology; Mice; Mice, Inbred BALB C; Mitochondria - drug effects; Mitochondria - physiology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Tumors
• ISSN: 0250-7005; 1791-7530

Background: Adriamycin (ADM) is a potent antitumor drug that induces apoptosis (AP) in tumor cells. AP is modulated by caspases and by mitogen-activated protein kinases (MAPK) as well as by the mitochondrial membrane potential (ΔΨ m ). We studied the participation of these systems in peritoneal macrophages from ADM-treated mice. Materials and Methods: Balb/c mice were either treated with ADM (5mg/kg, i.p.) or with 0.85% NaCl solution (controls). One hour later, peritoneal cells were harvested and cultured for 28 h. AP was evaluated by ethidium bromide and acridine orange staining; ΔΨ m was monitored using a MitoCapture stain Kit; DNA integrity was assessed by electrophoretic analysis. Animals were treated (i.p.) 1 h before ADM administration with Z-LEHD-FMK, Z-DEVD-FMK, or Z-VAD-FMK (caspase-9, caspases-3,7,10 and general caspase inhibitors, respectively) or with PD169316 (a MAPK p38 inhibitor). Results: ADM induced a higher rate of AP and the characteristic electrophoretic DNA ladder pattern. Mice treated with caspases inhibitors plus ADM showed significant reductions in AP and DNA laddering; in contrast, no differences were observed in mice treated with PD169316 plus ADM in comparison with ADM alone. ADM also induced early loss of the ΔΨ m . Conclusion: In these experimental conditions, ADM induced AP in a mainly caspase-9-dependent manner and this was related to a reduction in the ΔΨ m .