Dual targeting Bcl-2 and Bcl-xL augments osteosarcoma response to doxorubicin

Abstract

Chemotherapy resistance is the major cause of treatment failure in osteosarcoma, the most common primary bone malignancy, and sensitizing therapeutic strategy is required to improve the clinical outcome. In this study, we discovered that navitoclax, a selective inhibitor of Bcl-2/Bcl-xL, effectively combats chemoresistance in osteosarcoma. Our research revealed that Bcl-2, but not Bcl-xL, is upregulated in osteosarcoma cells that are resistant to doxorubicin. However, venetoclax, a specific inhibitor of Bcl-2, did not exhibit activity against doxorubicin-resistant cells. Further analysis showed that depleting either Bcl-2 or Bcl-xL alone was insufficient to overcome doxorubicin resistance. Only by depleting both Bcl-2 and Bcl-xL significantly reduce the viability of doxorubicin-resistant cells. Similarly, navitoclax not only decreased the viability of doxorubicin-resistant cells but also acted synergistically with doxorubicin in cells sensitive to the drug. To confirm the ability of navitoclax to overcome doxorubicin resistance, we conducted experiments using multiple mouse models of osteosarcoma, both doxorubicin-sensitive and doxorubicin-resistant. The results provided confirmation that navitoclax is effective in overcoming doxorubicin resistance. Our findings demonstrate that simultaneous inhibition of Bcl-2 and Bcl-xL could serve as a novel strategy to sensitize chemoresistant osteosarcoma cells. Moreover, our study presents preclinical evidence supporting the potential of a navitoclax and doxorubicin combination therapy for the treatment of osteosarcoma, paving the way for future clinical investigations.

Keywords:

• Osteosarcoma
• navitoclax
• venetoclax
• Bcl-2
• Bcl-xL
• synergism

Acknowledgements

Not applicable

Author contributions

CHC and YP conducted the experiments. HYY and HXQ supervised the project, analysed the data. All prepared manuscript and approved submission.

Availability of data and material

Data and materials are available upon request.

Disclosure statement

No potential conflict of interest was reported by the authors.

Informed consent

Not applicable

Research involving human participants and/or animals

This study was approved by the ethics committee of Hubei University of Art and Science (Approved No. 2018/2023-02). All procedures performed in studies involving human participants were in accordance with the ethical standards of Hubei University of Art and Science committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Funding

This work was supported by a research grant provided by Xiangyang Science and Technology Bureau (2021YL11).