title: Apoptosis therapy in cancer: the first single-molecule co-activating p53 and the translocator protein in glioblastoma.
abstract: In the complex scenario of cancer, treatment with compounds targeting multiple cell pathways has been emerging. In Glioblastoma Multiforme (GBM), p53 and Translocator Protein (TSPO), both acting as apoptosis inducers, represent two attractive intracellular targets. On this basis, novel indolylglyoxylyldipeptides, rationally designed to activate TSPO and p53, were synthesized and biologically characterized. The new compounds were able to bind TSPO and to reactivate p53 functionality, through the dissociation from its physiological inhibitor, murine double minute 2 (MDM2). In GBM cells, the new molecules caused Δψm dissipation and inhibition of cell viability. These effects resulted significantly higher with respect to those elicited by the single target reference standards applied alone, and coherent with the synergism resulting from the simultaneous activation of TSPO and p53. Taken together, these results suggest that TSPO/MDM2 dual-target ligands could represent a new attractive multi-modal opportunity for anti-cancer strategy in GBM.
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Da Pozzo
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giacomelli
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Rossi
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barresi
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Limatola
authors.affiliation: Dipartimento di Scienze Motorie, University of Naples "Parthenope", Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Lamberti
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D018079:Receptors, GABA / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D018079:Receptors, GABA; C499229:TSPO protein, human; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
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