title: Panobinostat synergizes with zoledronic acid in prostate cancer and multiple myeloma models by increasing ROS and modulating mevalonate and p38-MAPK pathways.
abstract: Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term responses to available therapies. The histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid malignancies and is currently in phase III trials for relapsed MM. Bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of bone metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status, androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage-independent agar assay in both ZOL-sensitive and ZOL-resistant cells and was confirmed in vivo in a PCa xenograft model. The co-administration of the antioxidant N-acetyl-L-cysteine blocked the increased reactive oxygen species generation and apoptosis observed in the combination setting compared with control or single-agent treatments, suggesting that oxidative injury plays a functional role in the synergism. Proapoptotic synergy was also partially antagonized by the addition of geranyl-geraniol, which bypasses the inhibition of farnesylpyrophosphate synthase by ZOL in the mevalonate pathway, supporting the involvement of this pathway in the synergy. Finally, at the molecular level, the inhibition of basal and ZOL-induced activation of p38-MAPK by panobinostat in sensitive and ZOL-resistant cells and in tumor xenografts could explain, at least in part, the observed synergism.
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale'-IRCCS, Napoli, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Bruzzese
authors.forename: B
authors.initials: B
authors.lastname: Pucci
authors.forename: M R
authors.initials: MR
authors.lastname: Milone
authors.forename: C
authors.initials: C
authors.lastname: Ciardiello
authors.forename: R
authors.initials: R
authors.lastname: Franco
authors.forename: M I
authors.initials: MI
authors.lastname: Chianese
authors.forename: M
authors.initials: M
authors.lastname: Rocco
authors.forename: E
authors.initials: E
authors.lastname: Di Gennaro
authors.forename: A
authors.initials: A
authors.lastname: Leone
authors.forename: A
authors.initials: A
authors.lastname: Luciano
authors.forename: C
authors.initials: C
authors.lastname: Arra
authors.forename: D
authors.initials: D
authors.lastname: Santini
authors.forename: M
authors.initials: M
authors.lastname: Caraglia
authors.forename: A
authors.initials: A
authors.lastname: Budillon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000077767:Panobinostat; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D006877:Hydroxamic Acids; D007093:Imidazoles; D007211:Indoles; D017382:Reactive Oxygen Species; D000077211:Zoledronic Acid; D000077767:Panobinostat; D048051:p38 Mitogen-Activated Protein Kinases; D008798:Mevalonic Acid