title: The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo.
abstract: KP1339 is a promising ruthenium-based anticancer compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of the parental compounds as compared to the drug combination was tested against a panel of cancer cell lines with a focus on hepatoma. Combination of KP1339 with sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both sorafenib-resistant as well as sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly, sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the ruthenium drug. In addition, sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the KP1339/sorafenib combination was evaluated in the Hep3B hepatoma xenograft. KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to sorafenib, which induced a 1.9-fold prolonged survival. The combined therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1 melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of KP1339 with sorafenib displays promising activity in vitro and in vivo especially against human hepatoma models.
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Austria; Comprehensive Cancer Center of the Medical University Vienna, Austria; Research and Platform "Translational Cancer Therapy Research" Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Bihter
authors.initials: B
authors.lastname: Atil
authors.forename: Kushtrim
authors.initials: K
authors.lastname: Kryeziu
authors.forename: Diana
authors.initials: D
authors.lastname: Groza
authors.forename: Gunda
authors.initials: G
authors.lastname: Koellensperger
authors.forename: Wilfried
authors.initials: W
authors.lastname: Körner
authors.forename: Ute
authors.initials: U
authors.lastname: Jungwirth
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D012428:Ruthenium / Q000494:pharmacology*; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: C551585:KP 1339; D009942:Organometallic Compounds; D010671:Phenylurea Compounds; D009536:Niacinamide; D012428:Ruthenium; D000077157:Sorafenib
keywords: Cell cycle arrest; Drug accumulation; P38; Ruthenium; STAT3; Sorafenib; Synergism