Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression

• Published in: Cancer chemotherapy and pharmacology Vol. 88; no. 3; pp. 513 - 524
• Main Authors: Sugiu, Kazuhisa, Tazawa, Hiroshi, Hasei, Joe, Yamakawa, Yasuaki, Omori, Toshinori, Komatsubara, Tadashi, Mochizuki, Yusuke, Kondo, Hiroya, Osaki, Shuhei, Fujiwara, Tomohiro, Yoshida, Aki, Kunisada, Toshiyuki, Ueda, Koji, Urata, Yasuo, Kagawa, Shunsuke, Ozaki, Toshifumi, Fujiwara, Toshiyoshi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2021; Springer Nature B.V
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Anticancer properties; Antitumor activity; Apoptosis; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily B - genetics; Biomedical materials; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - pathology; Bone tumors; Cancer Research; Cell Line, Tumor; Chemoresistance; Chemotherapy; Children; Doxorubicin; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; In vitro methods and tests; In vivo methods and tests; MDR1 protein; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; Multidrug resistance; Oncology; Oncolysis; Oncolytic Virotherapy - methods; Original Article; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - pathology; P-Glycoprotein; Pharmacology/Toxicology; Sarcoma; siRNA; Therapeutic targets; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; MDR1; Osteosarcoma; Chemoresistance; Oncolytic adenovirus; p53
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-021-04310-5

Background Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53–expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells. Materials and methods The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model. Results DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model. Conclusion Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.