Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression

Kazuhisa Sugiu, Hiroshi Tazawa, Jou Hasei, Yasuaki Yamakawa, Toshinori Omori, Tadashi Komatsubara, Yusuke Mochizuki, Hiroya Kondo, Shuhei Osaki, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Koji Ueda, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)513-524
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume88
Issue number3
DOIs
Publication statusPublished - Sep 2021

Keywords

  • Chemoresistance
  • MDR1
  • Oncolytic adenovirus
  • Osteosarcoma
  • p53

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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