TY - JOUR
T1 - Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression
AU - Sugiu, Kazuhisa
AU - Tazawa, Hiroshi
AU - Hasei, Jou
AU - Yamakawa, Yasuaki
AU - Omori, Toshinori
AU - Komatsubara, Tadashi
AU - Mochizuki, Yusuke
AU - Kondo, Hiroya
AU - Osaki, Shuhei
AU - Fujiwara, Tomohiro
AU - Yoshida, Aki
AU - Kunisada, Toshiyuki
AU - Ueda, Koji
AU - Urata, Yasuo
AU - Kagawa, Shunsuke
AU - Ozaki, Toshifumi
AU - Fujiwara, Toshiyoshi
N1 - Funding Information:
This study was supported in part by grants from the Japan Agency for Medical Research and Development (T. Fujiwara, No. 17ck0106285h001) and grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (T. Fujiwara, nos. 25293283 and 16H05416; T. Ozaki, no. 25293323; T. Kunisada, nos. 25462333 and 16K10862; K. Sugiu, no. 15K10446; and H. Tazawa, no. 16K10596).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Chemoresistance
KW - MDR1
KW - Oncolytic adenovirus
KW - Osteosarcoma
KW - p53
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U2 - 10.1007/s00280-021-04310-5
DO - 10.1007/s00280-021-04310-5
M3 - Article
C2 - 34114067
AN - SCOPUS:85107510534
SN - 0344-5704
VL - 88
SP - 513
EP - 524
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 3
ER -
