Synergistic Effects of a Smac Mimetic with Doxorubicin Against Human Osteosarcoma

• Published in: Anticancer research 2017-11, Vol.37 (11), p.6097
• Main Authors: Kamata, Etsuko, Kawamoto, Teruya, Ueha, Takeshi, Hara, Hitomi, Fukase, Naomasa, Minoda, Masaya, Morishita, Masayuki, Takemori, Toshiyuki, Fujiwara, Shuichi, Nishida, Kotaro, Kuroda, Ryosuke, Kurosaka, Masahiro, Akisue, Toshihiro
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Apoptosis - drug effects; Azocines - pharmacology; Benzhydryl Compounds - pharmacology; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Proliferation - drug effects; Doxorubicin - pharmacology; Drug Synergism; Drug Therapy, Combination; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Oligopeptides - pharmacology; Osteosarcoma - drug therapy; Osteosarcoma - metabolism; Osteosarcoma - pathology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.12058

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. 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. 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. 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.