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A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
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Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression

Kazuhisa Sugiu1, Hiroshi Tazawa2,3, Joe Hasei1

  • 1Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.

Cancer Chemotherapy and Pharmacology
|June 11, 2021
PubMed
Abstract

Insights

Oncolytic adenovirus OBP-702 sensitizes chemotherapy-refractory osteosarcoma (OS) to doxorubicin by suppressing multidrug resistant 1 (MDR1). Combination therapy significantly inhibited tumor growth in preclinical models.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Osteosarcoma (OS) is a bone cancer with poor prognosis in chemotherapy-refractory cases.
  • Oncolytic adenovirus OBP-702, engineered to express p53, shows antitumor effects.
  • Chemoresistance in OS is a significant clinical challenge.

Purpose of the Study:

  • To evaluate the chemosensitizing effect of OBP-702 in human osteosarcoma cells.
  • To investigate the role of multidrug resistant 1 (MDR1) in doxorubicin resistance.
  • To assess the efficacy of OBP-702 in combination with doxorubicin.

Main Methods:

  • In vitro and in vivo studies using parental and doxorubicin (DOX)-resistant OS cells (U2OS, MNNG/HOS).
  • Assessment of OBP-702 and DOX antitumor activities.
  • Evaluation of MDR1 expression and its modulation by OBP-702 and MDR1 siRNA.
  • Analysis of DOX-induced apoptosis and tumor growth in a xenograft model.

Main Results:

  • DOX-resistant OS cells showed high MDR1 expression, which was suppressed by OBP-702 or MDR1 siRNA.
  • OBP-702 treatment enhanced DOX-induced apoptosis in resistant cells.
  • Combination therapy of OBP-702 and DOX significantly suppressed tumor growth in vivo.

Conclusions:

  • MDR1 is a viable therapeutic target for overcoming chemoresistance in osteosarcoma.
  • Tumor-specific virotherapy with OBP-702 offers a promising strategy to reverse chemoresistance.
  • Suppression of MDR1 by OBP-702 is a key mechanism for chemosensitization in OS.
Keywords:
ChemoresistanceMDR1Oncolytic adenovirusOsteosarcomap53

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