title: The AKT/NF-κB inhibitor xanthohumol is a potent anti-lymphocytic leukemia drug overcoming chemoresistance and cell infiltration.
abstract: Although the vast majority of patients with acute lymphocytic leukemia (ALL) attain remission with modern therapies, relapsed leukemia will continue to be a common malignancy both in childhood and in adults, until new treatments are available. Therapeutic options for advanced B-cell acute lymphocytic leukemia are still limited and acquired drug resistance and extramedullary tissue infiltration are two major obstacles during treatment. The prenylflavonoid xanthohumol (XN) has shown in vitro and in vivo therapeutic potential against a range of tumors. In the present study we investigated the effects of XN on B-ALL cells in vitro and in an ALL-like xenograft mouse model. Treatment of ALL cell lines with XN resulted in growth arrest and apoptosis induction. XN retained its cytotoxicity when adriamycin resistant cells were examined while ALL cell clones adapted to long-term exposure to XN resulted highly responsive to cytotoxic drugs. Administration of 50μg XN/mouse (5 days/week) significantly increased animal life span by delaying the insurgence of neurological disorders due to leukemic cells dissemination. In agreement with a less invasive phenotype, cell migration and invasion were impaired by XN and basal levels of FAK, AKT and NF-κB signaling pathways were down-regulated in ALL cells upon XN exposure. Our data indicate that XN has significant antileukemic activity both in vitro and in vivo, which associates with impaired cell migration and invasion. Interestingly, this activity overcomes mechanisms leading to drug-resistance. XN represents a promising agent perspective for ALL therapy and recurrence prevention and would deserve clinical testing in the near future.
authors.affiliation: Immunology, IRCCS Azienda Ospedaliera Universitaria San Martino, IST - Istituto Nazionale per la Ricerca sul Cancro, Largo R.Benzi 10, 16132 Genova, Italy. roberto.benelli@istge.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Benelli
authors.forename: Roberta
authors.initials: R
authors.lastname: Venè
authors.forename: Monica
authors.initials: M
authors.lastname: Ciarlo
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Carlone
authors.forename: Ottavia
authors.initials: O
authors.lastname: Barbieri
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D017254:Leukemic Infiltration / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D011427:Propiophenones / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
chemical_list: D005419:Flavonoids; D016328:NF-kappa B; D011427:Propiophenones; D051057:Proto-Oncogene Proteins c-akt; C104536:xanthohumol