title: Organometallic iron(III)-salophene exerts cytotoxic properties in neuroblastoma cells via MAPK activation and ROS generation.
abstract: The objective of the present study was to investigate the specific effects of Iron(III)-salophene (Fe-SP) on viability, morphology, proliferation, cell cycle progression, ROS generation and pro-apoptotic MAPK activation in neuroblastoma (NB) cells. A NCI-DTP cancer screen revealed that Fe-SP displayed high toxicity against cell lines of different tumor origin but not tumor type-specificity. In a viability screen Fe-SP exhibited high cytotoxicity against all three NB cell lines tested. The compound caused cell cycle arrest in G1 phase, suppression of cells progressing through S phase, morphological changes, disruption of the mitochondrial membrane depolarization potential, induction of apoptotic markers as well as p38 and JNK MAPK activation, DNA degradation, and elevated generation of reactive oxygen species (ROS) in SMS-KCNR NB cells. In contrast to Fe-SP, non-complexed salophene or Cu(II)-SP did not raise ROS levels in NB or SKOV-3 ovarian cancer control cells. Cytotoxicity of Fe-SP and activation of caspase-3, -7, PARP, pro-apoptotic p38 and JNK MAPK could be prevented by co-treatment with antioxidants suggesting ROS generation is the primary mechanism of cytotoxic action. We report here that Fe-SP is a potent growth-suppressing and cytotoxic agent for in vitro NB cell lines and, due to its high tolerance in previous animal toxicity studies, a potential therapeutic drug to treat NB tumors in vivo.
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School, Brown University, Providence, Rhode Island, United States of America. kkim@wihri.org
authors.forename: Kyu Kwang
authors.initials: KK
authors.lastname: Kim
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strongin
authors.forename: Richard G
authors.initials: RG
authors.lastname: Moore
authors.forename: Laurent
authors.initials: L
authors.lastname: Brard
authors.forename: Thilo S
authors.initials: TS
authors.lastname: Lange
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D005290:Ferric Compounds / Q000737:chemistry*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008564:Membrane Potentials; D009447:Neuroblastoma / Q000201:enzymology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005290:Ferric Compounds; C530921:Iron(III)-salophene; D017382:Reactive Oxygen Species; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053179:Caspase 7