Michael Berger1, Olaf Neth2, Matthias Ilmer3, Agnès Garnier4, Manuel Vicente Salinas-Martín5, Juan Carlos de Agustín Asencio6, Dietrich von Schweinitz4, Roland Kappler4, Miguel Muñoz7. 1. Division of Pediatric Infectious Disease and Immunopathology, Virgen del Rocío Children's Hospital, Institute of Biomedicine, Seville, Spain; Department of Pediatric Surgery, Research Laboratories, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Germany. 2. Division of Pediatric Infectious Disease and Immunopathology, Virgen del Rocío Children's Hospital, Institute of Biomedicine, Seville, Spain. 3. Department of Translational Molecular Pathology, MD Anderson Cancer Center, University of Texas Health Science Center at Houston, TX, USA. 4. Department of Pediatric Surgery, Research Laboratories, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Germany. 5. Department of Pathology, Juan Ramón Jiménez Hospital, Huelva, Spain. 6. Department of Pediatric Surgery, Virgen del Rocío Children's Hospital, Seville, Spain. 7. Research Laboratory on Neuropeptides, Virgen del Rocío Children's Hospital, Seville, Spain. Electronic address: mmunoz@cica.es.
Abstract
BACKGROUND & AIMS: Multidrug resistance presents a major problem in hepatoblastoma (HB), and new anti-tumor strategies are desperately needed. The substance P (SP)/neurokinin-1 receptor (NK1R) complex has been discovered to be pivotal in the development of a variety of human cancers, and NK1R antagonists, such as the clinical drug aprepitant, are promising future anticancer agents. Yet, the role of the SP/NK1R complex as a potential anticancer target in HB is unknown. METHODS: Human HB cell lines HepT1, HepG2, and HuH6, human tumor samples from 17 children with HB as well as mice xenografted with human HB cell line HuH6 were analyzed regarding the SP/NK1R complex as a potential new anti-tumor target in HB. RESULTS: Therapeutic targeting with the NK1R antagonists aprepitant, L-733,060, and L-732,138 led to growth inhibition and apoptosis in HepT1, HepG2, and HuH6 cells in a dose-dependent manner. Intriguingly, HB cells predominantly expressed the truncated splice variant of NK1R. Human fibroblasts showed only dismal NK1R expression and were significantly more resistant. Stimulation of HB cells with SP, NK1R's natural ligand, caused increased growth rates and abrogated the anti-proliferative effect of NK1R antagonists. Expression analysis of 17 human HB samples confirmed the clinical relevance of NK1R. Most importantly, oral treatment of a HuH6 xenograft mouse model with 80mg/kg/day aprepitant for 24days resulted in a striking reduction of tumor growth, as evidenced by reduced tumor volume and weight, lowered tumor-specific alpha-fetoprotein (AFP) serum levels, and decreased number of Ki-67 positive cells. Furthermore, aprepitant treatment inhibited in vivo angiogenesis. CONCLUSIONS: For the first time, we describe the NK1R in its truncated splice variant as a potent target in human HB and an inhibitory effect in vivo and in vitro by NK1R antagonists. Therefore, NK1R antagonists should be considered promising new candidates for innovative therapeutic strategies against HB.
BACKGROUND & AIMS: Multidrug resistance presents a major problem in hepatoblastoma (HB), and new anti-tumor strategies are desperately needed. The substance P (SP)/neurokinin-1 receptor (NK1R) complex has been discovered to be pivotal in the development of a variety of humancancers, and NK1R antagonists, such as the clinical drug aprepitant, are promising future anticancer agents. Yet, the role of the SP/NK1R complex as a potential anticancer target in HB is unknown. METHODS:Human HB cell lines HepT1, HepG2, and HuH6, humantumor samples from 17 children with HB as well as mice xenografted with human HB cell line HuH6 were analyzed regarding the SP/NK1R complex as a potential new anti-tumor target in HB. RESULTS: Therapeutic targeting with the NK1R antagonists aprepitant, L-733,060, and L-732,138 led to growth inhibition and apoptosis in HepT1, HepG2, and HuH6 cells in a dose-dependent manner. Intriguingly, HB cells predominantly expressed the truncated splice variant of NK1R. Human fibroblasts showed only dismal NK1R expression and were significantly more resistant. Stimulation of HB cells with SP, NK1R's natural ligand, caused increased growth rates and abrogated the anti-proliferative effect of NK1R antagonists. Expression analysis of 17 human HB samples confirmed the clinical relevance of NK1R. Most importantly, oral treatment of a HuH6 xenograft mouse model with 80mg/kg/day aprepitant for 24days resulted in a striking reduction of tumor growth, as evidenced by reduced tumor volume and weight, lowered tumor-specific alpha-fetoprotein (AFP) serum levels, and decreased number of Ki-67 positive cells. Furthermore, aprepitant treatment inhibited in vivo angiogenesis. CONCLUSIONS: For the first time, we describe the NK1R in its truncated splice variant as a potent target in human HB and an inhibitory effect in vivo and in vitro by NK1R antagonists. Therefore, NK1R antagonists should be considered promising new candidates for innovative therapeutic strategies against HB.
Authors: Agnès Garnier; Matthias Ilmer; Kristina Becker; Beate Häberle; Dietrich VON Schweinitz; Roland Kappler; Michael Berger Journal: Oncol Lett Date: 2015-11-20 Impact factor: 2.967
Authors: A Molinos-Quintana; P Trujillo-Hacha; J I Piruat; J A Bejarano-García; E García-Guerrero; J A Pérez-Simón; Miguel Muñoz Journal: Invest New Drugs Date: 2018-05-02 Impact factor: 3.850