Kentaro Igarashi1,2,3, Kei Kawaguchi1,2, Tasuku Kiyuna1,2, Takashi Murakami1,2, Norio Yamamoto3, Katsuhiro Hayashi3, Hiroaki Kimura3, Shinji Miwa3, Hiroyuki Tsuchiya4, Robert M Hoffman5,2. 1. AntiCancer, Inc., San Diego, CA, U.S.A. 2. Department of Surgery, University of California, San Diego, CA, U.S.A. 3. Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan. 4. Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan all@anticancer.com tsuchi@med.kanazawa-u.ac.jp. 5. AntiCancer, Inc., San Diego, CA, U.S.A. all@anticancer.com tsuchi@med.kanazawa-u.ac.jp.
Abstract
AIM: We have previously reported that caffeine can enhance chemotherapy efficacy of bone and soft tissue sarcoma via cell-cycle perturbation. Valproic acid has histone deacetylase (HDAC) inhibitory activity. We have also reported the anti-tumor efficacy of combination treatment with caffeine and valproic acid against osteosarcoma primary tumors in a cell-line orthotopic mouse model. MATERIALS AND METHODS: In this study, we performed combination treatment of caffeine and valproic acid on osteosarcoma cell lines in vitro and in spontaneous and experimental lung metastasis mouse models of osteosarcoma. Survival of 143B-RFP human osteosarcoma cells after exposure to caffeine and valproic acid for 72 hours was determined using the WST-8 assay. IC50 values and combination indices were calculated. Mouse models of primary osteosarcoma and spontaneous lung metastasis were obtained by orthotopic intra-tibial injection of 143B-RFP cells. Valproic acid, caffeine, and combination of both drugs were administered from day 7, five times a week, for four weeks. Six weeks after orthotopic injection, lung samples were excised and observed with a fluorescence imaging system. A mouse model of experimental lung metastasis was obtained by tail vein injection of 143B-RFP cells. The mice were treated with these agents from day 0, five times a week for four weeks. RESULTS: Both caffeine and valproic acid caused concentration-dependent cell kill in vitro. Synergistic efficacy of the combination treatment was observed. In the spontaneous lung-metastasis model, the number of lung metastasis was 9.0±2.6 in the untreated group (G1); 10.8±2.9 in the caffeine group (G2); 10.0±3.1 in the valproic-acid group (G3); and 3.0±1.1 in the combination group (G4); (p=6.78E-5 control vs. combination; p=0.006 valproic acid vs. combination; p=0.003 caffeine vs. combination). In the experimental lung-metastasis model, the combination group significantly reduced lung metastases and improved overall survival (p=0.0005). CONCLUSION: Efficacy of the combination of caffeine and valproic acid was observed in vitro and in spontaneous and experimental lung-metastasis mouse models of osteosarcoma. Copyright
AIM: We have previously reported that caffeine can enhance chemotherapy efficacy of bone and soft tissue sarcoma via cell-cycle perturbation. Valproic acid has histone deacetylase (HDAC) inhibitory activity. We have also reported the anti-tumor efficacy of combination treatment with caffeine and valproic acid against osteosarcoma primary tumors in a cell-line orthotopic mouse model. MATERIALS AND METHODS: In this study, we performed combination treatment of caffeine and valproic acid on osteosarcoma cell lines in vitro and in spontaneous and experimental lung metastasis mouse models of osteosarcoma. Survival of 143B-RFP humanosteosarcoma cells after exposure to caffeine and valproic acid for 72 hours was determined using the WST-8 assay. IC50 values and combination indices were calculated. Mouse models of primary osteosarcoma and spontaneous lung metastasis were obtained by orthotopic intra-tibial injection of 143B-RFP cells. Valproic acid, caffeine, and combination of both drugs were administered from day 7, five times a week, for four weeks. Six weeks after orthotopic injection, lung samples were excised and observed with a fluorescence imaging system. A mouse model of experimental lung metastasis was obtained by tail vein injection of 143B-RFP cells. The mice were treated with these agents from day 0, five times a week for four weeks. RESULTS: Both caffeine and valproic acid caused concentration-dependent cell kill in vitro. Synergistic efficacy of the combination treatment was observed. In the spontaneous lung-metastasis model, the number of lung metastasis was 9.0±2.6 in the untreated group (G1); 10.8±2.9 in the caffeine group (G2); 10.0±3.1 in the valproic-acid group (G3); and 3.0±1.1 in the combination group (G4); (p=6.78E-5 control vs. combination; p=0.006 valproic acid vs. combination; p=0.003 caffeine vs. combination). In the experimental lung-metastasis model, the combination group significantly reduced lung metastases and improved overall survival (p=0.0005). CONCLUSION: Efficacy of the combination of caffeine and valproic acid was observed in vitro and in spontaneous and experimental lung-metastasis mouse models of osteosarcoma. Copyright
Authors: Mio Yanagisawa; Alicia A Gingrich; Sean Judge; Chin-Shang Li; Nana Wang; Steven W Thorpe; Amanda R Kirane; Richard J Bold; Arta M Monjazeb; Robert J Canter Journal: Anticancer Res Date: 2018-03 Impact factor: 2.480
Authors: Shamini Murugavel; Antoinette Bugyei-Twum; Pratiek N Matkar; Husain Al-Mubarak; Hao H Chen; Mohamed Adam; Shubha Jain; Tanya Narang; Rawand M Abdin; Mohammad Qadura; Kim A Connelly; Howard Leong-Poi; Krishna K Singh Journal: Front Pharmacol Date: 2018-07-11 Impact factor: 5.810