Etsuko Kamata1, Teruya Kawamoto2,3, Takeshi Ueha4, Hitomi Hara1, Naomasa Fukase1, Masaya Minoda1, Masayuki Morishita1, Toshiyuki Takemori1, Shuichi Fujiwara1, Kotaro Nishida1, Ryosuke Kuroda1, Masahiro Kurosaka1, Toshihiro Akisue1,5. 1. Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan. 2. Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan trykwmt@med.kobe-u.ac.jp. 3. Division of Orthopaedic Surgery, Kobe University International Clinical Cancer Research Center, Kobe, Japan. 4. Division of Rehabilitation Medicine, Kobe University Graduate School of Medicine, Kobe, Japan. 5. Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.
Abstract
BACKGROUND/AIM: Second mitochondria-derived activator of caspase (Smac) is a proapoptogenic mitochondrial protein that antagonizes inhibitors of apoptosis proteins (IAPs), resulting in induction of apoptosis. In the present study we investigated the effects of a Smac mimetic in combination with doxorubicin against osteosarcoma. MATERIALS AND METHODS: In vitro effects of the combination of a Smac mimetic AT-406 and doxorubicin on cell proliferation and apoptosis in osteosarcoma cell lines were examined using cell proliferation assays, flow cytometry, and immunoblot analyses. For in vivo experiments, human osteosarcoma xenografts were treated with combination of the two substances, and tumor volume and apoptotic activity in treated tumors were assessed. RESULTS: In vitro studies revealed that combination of the two substances significantly inhibited osteosarcoma proliferation with decreased cIAP1 expression and induced apoptosis in osteosarcoma cells. Combination of the two substances significantly suppressed osteosarcoma growth in vivo. Moreover, decreased cIAP1 expression and increased apoptotic activity were observed in tumors treated by their combination of the substances. CONCLUSION: The Smac mimetic AT-406 showed an apoptotic effect and a synergistic antitumor effect with doxorubicin on osteosarcoma. The combination of AT-406 and doxorubicin may serve as a novel therapeutic strategy for osteosarcoma treatment. Copyright
BACKGROUND/AIM: Second mitochondria-derived activator of caspase (Smac) is a proapoptogenic mitochondrial protein that antagonizes inhibitors of apoptosis proteins (IAPs), resulting in induction of apoptosis. In the present study we investigated the effects of a Smac mimetic in combination with doxorubicin against osteosarcoma. MATERIALS AND METHODS: In vitro effects of the combination of a Smac mimetic AT-406 and doxorubicin on cell proliferation and apoptosis in osteosarcoma cell lines were examined using cell proliferation assays, flow cytometry, and immunoblot analyses. For in vivo experiments, humanosteosarcoma xenografts were treated with combination of the two substances, and tumor volume and apoptotic activity in treated tumors were assessed. RESULTS: In vitro studies revealed that combination of the two substances significantly inhibited osteosarcoma proliferation with decreased cIAP1 expression and induced apoptosis in osteosarcoma cells. Combination of the two substances significantly suppressed osteosarcoma growth in vivo. Moreover, decreased cIAP1 expression and increased apoptotic activity were observed in tumors treated by their combination of the substances. CONCLUSION: The Smac mimetic AT-406 showed an apoptotic effect and a synergistic antitumor effect with doxorubicin on osteosarcoma. The combination of AT-406 and doxorubicin may serve as a novel therapeutic strategy for osteosarcoma treatment. Copyright
Keywords:
Osteosarcoma; apoptosis; cellular inhibitor of apoptosis protein 1 (cIAP1); doxorubicin; second mitochondria-derived activator of caspase (Smac)
Authors: Paul A Townsend; Maria V Kozhevnikova; Olivier N F Cexus; Andrey A Zamyatnin; Surinder M Soond Journal: J Exp Clin Cancer Res Date: 2021-11-09