Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression
Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression
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DOI：
10.1007/s00280-021-04310-5
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发表时间：
2021-06
影响因子：
3
通讯作者：
K. Sugiu;H. Tazawa;J. Hasei;Y. Yamakawa;Toshinori Omori;Tadashi Komatsubara;Yusuke Mochizuki;Hiroya Kondo;Shuhei Osaki;T. Fujiwara;Aki Yoshida;T. Kunisada;K. Ueda;Y. Urata;S. Kagawa;T. Ozaki;T. Fujiwara
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文献类型：
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作者：
K. Sugiu;H. Tazawa;J. Hasei;Y. Yamakawa;Toshinori Omori;Tadashi Komatsubara;Yusuke Mochizuki;Hiroya Kondo;Shuhei Osaki;T. Fujiwara;Aki Yoshida;T. Kunisada;K. Ueda;Y. Urata;S. Kagawa;T. Ozaki;T. Fujiwara
骨肉瘤（Osteosarcoma，OS）是一种多发于儿童和青少年的恶性骨肿瘤.化疗难治性OS患者预后差。我们开发了一种表达抑癌基因p53的溶瘤腺病毒（OBP-702），对人OS细胞具有抗肿瘤作用。在这里，我们证明了OBP-702在人OS细胞中的化学增敏作用。材料和方法使用亲本和阿霉素耐药OS细胞评估阿霉素（DOX）和OBP-702的体外和体内抗肿瘤活性（U2 OS，MNNG/HOS）和阿霉素耐药MNNG/HOS异种移植瘤模型。OBP-702或MDR 1 siRNA可抑制OBP-702的表达，增强DOX诱导的细胞凋亡。与单药治疗相比，OBP-702和DOX联合治疗可显着抑制DOX耐药MNNG/HOS异种移植肿瘤模型中的肿瘤生长。结论我们的研究结果表明，MDR 1是化疗耐药OS的一个有吸引力的治疗靶点。因此，肿瘤特异性病毒治疗是一种通过抑制MDR 1表达来逆转OS患者化疗耐药性的有前途的策略。
BackgroundOsteosarcoma (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 methodsThe 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.ResultsDOX-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.ConclusionOur 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.