Takashi Kobayashi1, Masayuki Kubota2,3, Yoshiaki Kinoshita2, Yuki Arai2, Toshiyuki Oyama2, Naoki Yokota2, Koichi Saito2, Yasunobu Matsuda4, Mami Osawa5. 1. Department of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata, 951-8510, Japan. kobataka@med.niigata-u.ac.jp. 2. Department of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata, 951-8510, Japan. 3. Kokuraminami Medical Care Hospital, 2-14-2 Kuzuharahigashi, Kokuraminami-ku, Kitakyu-syu, 800-0206, Japan. 4. Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-Dori, Chuo-ku, Niigata, 951-8518, Japan. 5. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata, 951-8510, Japan.
Abstract
PURPOSE: To investigate the possibility that the antioxidant stress protein Heme oxygenase-1 (HO-1) is involved in the acquisition of chemoresistance in cisplatin and pirarubicin (CITA) therapy. METHODS: Human hepatoblastoma-derived cell line (HepG2) was used to generate a knockdown cell line of HO-1 by small interfering RNA (siRNA). Expression of HO-1, epidermal growth factor receptor (EGFR), Akt, and extracellular signal-regulated kinase1/2 (ERK1/2) was examined by Western blot. The cytotoxic effect of cisplatin, pirarubicin, and EGFR inhibitor was examined by trypan blue staining. In human hepatoblastoma specimens (n = 5), changes of HO-1 expression were examined immunohistochemically before and after CITA therapy. RESULTS: HO-1 expression in HepG2 cells was increased by the treatment of cisplatin (CDDP) and pirarubicin (THP) dose-dependently. In HO-1 knockdown HepG2 cells, the HO-1 was not expressed and the percentage of trypan blue-positive cells (dead cells) was significantly increased after treatment of CDDP and THP. The EGFR inhibitor decreased the levels of HO-1, phospho-Akt and phospho-ERK1/2 in HepG2 cells. Combination treatment of EGFR inhibitor with CDDP and THP increased the cytotoxic effect in HepG2 cells. In human hepatoblastoma specimens, 4 of the 5 patients (80%) showed HO-1 expression changed much stronger in the viable tumor cells after CITA therapy. CONCLUSION: The cytotoxic effects of CDDP and THP were both enhanced under HO-1 knockdown conditions as well as under conditions that inhibit the activation pathway of HO-1 by EGFR inhibitors. EGFR/HO-1 axis may be involved in acquiring chemoresistance in HepG2 cell lines as well as in human hepatoblastoma.
PURPOSE: To investigate the possibility that the antioxidant stress protein Heme oxygenase-1 (HO-1) is involved in the acquisition of chemoresistance in cisplatin and pirarubicin (CITA) therapy. METHODS:Humanhepatoblastoma-derived cell line (HepG2) was used to generate a knockdown cell line of HO-1 by small interfering RNA (siRNA). Expression of HO-1, epidermal growth factor receptor (EGFR), Akt, and extracellular signal-regulated kinase1/2 (ERK1/2) was examined by Western blot. The cytotoxic effect of cisplatin, pirarubicin, and EGFR inhibitor was examined by trypan blue staining. In humanhepatoblastoma specimens (n = 5), changes of HO-1 expression were examined immunohistochemically before and after CITA therapy. RESULTS:HO-1 expression in HepG2 cells was increased by the treatment of cisplatin (CDDP) and pirarubicin (THP) dose-dependently. In HO-1 knockdown HepG2 cells, the HO-1 was not expressed and the percentage of trypan blue-positive cells (dead cells) was significantly increased after treatment of CDDP and THP. The EGFR inhibitor decreased the levels of HO-1, phospho-Akt and phospho-ERK1/2 in HepG2 cells. Combination treatment of EGFR inhibitor with CDDP and THP increased the cytotoxic effect in HepG2 cells. In humanhepatoblastoma specimens, 4 of the 5 patients (80%) showed HO-1 expression changed much stronger in the viable tumor cells after CITA therapy. CONCLUSION: The cytotoxic effects of CDDP and THP were both enhanced under HO-1 knockdown conditions as well as under conditions that inhibit the activation pathway of HO-1 by EGFR inhibitors. EGFR/HO-1 axis may be involved in acquiring chemoresistance in HepG2 cell lines as well as in humanhepatoblastoma.
Authors: Angelica Nogueira-Rodrigues; Giulliana Moralez; Rachele Grazziotin; Claudio C Carmo; Isabele A Small; Flavia V G Alves; Marcelo Mamede; Felipe Erlich; Celia Viegas; Sergio A Triginelli; Carlos G Ferreira Journal: Cancer Date: 2014-03-10 Impact factor: 6.860
Authors: József Zsiros; Laurence Brugieres; Penelope Brock; Derek Roebuck; Rudolf Maibach; Arthur Zimmermann; Margaret Childs; Daniele Pariente; Veronique Laithier; Jean-Bernard Otte; Sophie Branchereau; Daniel Aronson; Arun Rangaswami; Milind Ronghe; Michela Casanova; Michael Sullivan; Bruce Morland; Piotr Czauderna; Giorgio Perilongo Journal: Lancet Oncol Date: 2013-07-04 Impact factor: 41.316