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Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures

  • Authors:
    • Birgit Lohberger
    • Dietmar Glaenzer
    • Nicole Eck
    • Bibiane Steinecker-Frohnwieser
    • Andreas Leithner
    • Beate Rinner
    • Sylvia Kerschbaum-Gruber
    • Dietmar Georg
  • View Affiliations / Copyright

    Affiliations: Department of Orthopedics and Trauma, Medical University of Graz, A-8036 Graz, Austria, Department for Rehabilitation, Ludwig Boltzmann Institute for Arthritis and Rehabilitation, A-5760 Saalfelden, Austria, Division of Biomedical Research, Medical University of Graz, A-8036 Graz, Austria, Department of Radiation Oncology, Medical University of Vienna, A-1090 Vienna, Austria
    Copyright: © Lohberger et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 428
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    Published online on: March 30, 2021
       https://doi.org/10.3892/ol.2021.12689
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Abstract

Chondrosarcomas represent a heterogeneous group of primary bone cancers that are characterized by hyaline cartilaginous neoplastic tissue and are predominantly resistant to radiation and chemotherapy. However, adjuvant radiotherapy is often recommended in inoperable cases or after incomplete resections. To improve the efficiency of treatment, the present study tested a combination therapy with ionizing radiation (IR) and the proteasome inhibitor bortezomib. Using a three‑dimensional (3D) spheroid model, 0‑20 Gy of IR was applied to chondrosarcoma cells and healthy human chondrocytes. Following combined treatment with IR and bortezomib, the cell cycle distribution, apoptotic induction, the survivin pathway, autophagy and DNA damage were evaluated. Both cell types exhibited a slight decrease in viability following increasing doses of IR; the chondrosarcoma cells demonstrated a significant dose‑dependent increase in the expression levels of the DNA damage marker histone H2AX phosphorylation at serine 139 (γH2AX). The combination treatment with bortezomib significantly decreased the cell viability after 48 h compared with that in irradiated cells. High‑dose IR induced a G2/M phase arrest, which was accompanied by a decrease in the number of cells at the G1 and S phase. Co‑treatment with bortezomib changed the distribution of the cell cycle phases. The mRNA expression levels of the proapoptotic genes Bcl‑2‑associated X protein (Bax) and Bak were significantly increased by bortezomib treatment and combination therapy with IR. In addition, the combination therapy resulted in a synergistic decrease of the expression levels of survivin and its corresponding downstream pathway molecules, including heat shock protein 90, X‑linked inhibitor of apoptosis protein, smad 2 and smad 3. Comparative analyses of γH2AX at 1 and 24 h post‑IR revealed efficient DNA repair in human chondrosarcoma cells. Therefore, additional bortezomib treatment may only temporarily improve the radiation sensitivity of chondrosarcoma cells. However, the inhibition of the survivin pathway by the combined treatment with IR and bortezomib, observed in the present study, revealed a novel aspect in the tumor biology of chondrosarcoma 3D spheroid cultures and may represent a potential target for therapy.
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Copy and paste a formatted citation
Spandidos Publications style
Lohberger B, Glaenzer D, Eck N, Steinecker-Frohnwieser B, Leithner A, Rinner B, Kerschbaum-Gruber S and Georg D: Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures. Oncol Lett 21: 428, 2021.
APA
Lohberger, B., Glaenzer, D., Eck, N., Steinecker-Frohnwieser, B., Leithner, A., Rinner, B. ... Georg, D. (2021). Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures. Oncology Letters, 21, 428. https://doi.org/10.3892/ol.2021.12689
MLA
Lohberger, B., Glaenzer, D., Eck, N., Steinecker-Frohnwieser, B., Leithner, A., Rinner, B., Kerschbaum-Gruber, S., Georg, D."Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures". Oncology Letters 21.6 (2021): 428.
Chicago
Lohberger, B., Glaenzer, D., Eck, N., Steinecker-Frohnwieser, B., Leithner, A., Rinner, B., Kerschbaum-Gruber, S., Georg, D."Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures". Oncology Letters 21, no. 6 (2021): 428. https://doi.org/10.3892/ol.2021.12689
Copy and paste a formatted citation
x
Spandidos Publications style
Lohberger B, Glaenzer D, Eck N, Steinecker-Frohnwieser B, Leithner A, Rinner B, Kerschbaum-Gruber S and Georg D: Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures. Oncol Lett 21: 428, 2021.
APA
Lohberger, B., Glaenzer, D., Eck, N., Steinecker-Frohnwieser, B., Leithner, A., Rinner, B. ... Georg, D. (2021). Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures. Oncology Letters, 21, 428. https://doi.org/10.3892/ol.2021.12689
MLA
Lohberger, B., Glaenzer, D., Eck, N., Steinecker-Frohnwieser, B., Leithner, A., Rinner, B., Kerschbaum-Gruber, S., Georg, D."Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures". Oncology Letters 21.6 (2021): 428.
Chicago
Lohberger, B., Glaenzer, D., Eck, N., Steinecker-Frohnwieser, B., Leithner, A., Rinner, B., Kerschbaum-Gruber, S., Georg, D."Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures". Oncology Letters 21, no. 6 (2021): 428. https://doi.org/10.3892/ol.2021.12689
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