title: Involvement of p53 in specific anti-neuroectodermal tumor activity of aloe-emodin.
abstract: Previously, we have identified aloe-emodin (AE) as a new type of anticancer agent, with activity that is based on apoptotic cell death promoted by a neuroectodermal tumor-specific drug uptake. We attempt to clarify the intracellular target of AE and the apoptosis-signaling pathway activated by AE in neuroblastoma cell lines. Two-photon excitation microscopy and spectroscopic titrations documented that AE is highly concentrated in susceptible cells and binds to DNA. One of the most important mediators of apoptotic response to genotoxic stimuli, such as anticancer agents, is the p53 tumor suppressor gene. To evaluate the role played by p53 in AE-induced apoptosis a p53 mutant cell line, which lacks transcriptional activity of p53 targeted genes, was tested. AE displayed a reduced growth inhibitory and pro-apoptotic activity in p53 mutant cells (SK-N-BE(2c)) with respect to the p53 wild-type line (SJ-N-KP). This effect was not caused by a reduced drug uptake in the mutant neuroblastoma cell line but was related to a different apoptotic cell phenotype. Whereas SJ-N-KP cells were susceptible to a p53 transcription-dependent pathway of apoptosis, SK-N-BE(2c) cells underwent apoptosis with up-regulation of p53 expression but not of p53-target genes. After AE treatment p53 translocates to the mitochondria inter-membrane space in both neuroblastoma cell lines. Due to its high accumulation in neuroectodermal tumor cells AE could also kill tumor cells harboring p53 mutant genes. This property would further contribute to AE specific anti-tumor activity and might be exploitable in the clinic.
authors.affiliation: Department of Histology, Microbiology and Medical Biotechnology, University of Padova, Padua, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Pecere
authors.forename: Federica
authors.initials: F
authors.lastname: Sarinella
authors.forename: Cristiano
authors.initials: C
authors.lastname: Salata
authors.forename: Barbara
authors.initials: B
authors.lastname: Gatto
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bet
authors.forename: Francesca
authors.initials: F
authors.lastname: Dalla Vecchia
authors.forename: Alberto
authors.initials: A
authors.lastname: Diaspro
authors.forename: Modesto
authors.initials: M
authors.lastname: Carli
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
mesh_terms: D000880:Anthraquinones; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002675:Child, Preschool; D045304:Cytochromes c / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004642:Emodin / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2 / Q000502:physiology; D006801:Humans; D008297:Male; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D017599:Neuroectodermal Tumors / Q000188:drug therapy* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000880:Anthraquinones; D052160:Benzothiazoles; D017931:DNA Primers; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D045304:Cytochromes c; C518327:aloe emodin; C121565:pifithrin; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D004250:DNA Topoisomerases, Type II; D004642:Emodin