Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells.
Salinomycin is a polyether antibiotic isolated from Streptomyces albus that acts in different biological membranes as a ionophore with a preference for potassium. It is widely used as an anticoccidial drug in poultry and is fed to ruminants to improve nutrient absorption and feed efficiency. Salinomycin has recently been shown to selectively deplete human breast cancer stem cells from tumorspheres and to inhibit breast cancer growth and metastasis in mice. We show here that salinomycin induces massive apoptosis in human cancer cells of different origin, but not in normal cells such as human T lymphocytes. Moreover, salinomycin is able to induce apoptosis in cancer cells that exhibit resistance to apoptosis and anticancer agents by overexpression of Bcl-2, P-glycoprotein or 26S proteasomes with enhanced proteolytic activity. Salinomycin activates a distinct apoptotic pathway that is not accompanied by cell cycle arrest and that is independent of tumor suppressor protein p53, caspase activation, the CD95/CD95L system and the proteasome. Thus, salinomycin should be considered as a novel and effective anticancer agent that overcomes multiple mechanisms of apoptosis resistance in human cancer cells.
Fuchs
Dominik
D
Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
Heinold
Andreas
A
Opelz
Gerhard
G
Daniel
Volker
V
Naujokat
Cord
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011714:Pyrans / Q000494:pharmacology*; D000095662:Polyether Polyketides
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2; D011714:Pyrans; C010327:salinomycin; D000095662:Polyether Polyketides; C061553:ATP dependent 26S protease