Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition
Abstract Background Osteosarcoma is the most frequent primary malignant bone tumor. Although survival has distinctly increased due to neoadjuvant chemotherapy in the past, patients with metastatic disease and poor response to chemotherapy still have an adverse prognosis. Hence, development of new th...
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doaj-572afccbcf204f4ba0e2b876faa027d72020-11-25T01:59:16ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662017-04-0136111310.1186/s13046-017-0527-zDistinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibitionBernd Kubista0Thomas Schoefl1Lisa Mayr2Sushilla van Schoonhoven3Petra Heffeter4Reinhard Windhager5Bernhard K. Keppler6Walter Berger7Department of Orthopedics, Medical University of ViennaDepartment of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University ViennaDepartment of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University ViennaDepartment of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University ViennaDepartment of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University ViennaDepartment of Orthopedics, Medical University of ViennaResearch Platform “Translational Cancer Therapy Research”, University Vienna and Medical University ViennaDepartment of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University ViennaAbstract Background Osteosarcoma is the most frequent primary malignant bone tumor. Although survival has distinctly increased due to neoadjuvant chemotherapy in the past, patients with metastatic disease and poor response to chemotherapy still have an adverse prognosis. Hence, development of new therapeutic strategies is still of utmost importance. Methods Anticancer activity of KP46 against osteosarcoma cell models was evaluated as single agent and in combination approaches with chemotherapeutics and Bcl-2 inhibitors using MTT assay. Underlying mechanisms were tested by cell cycle, apoptosis and autophagy assays. Results KP46 exerted exceptional anticancer activity at the nanomolar to low micromolar range, depending on the assay format, against all osteosarcoma cell models with minor but significant differences in IC50 values. KP46 treatment of osteosarcoma cells caused rapid loss of cell adhesion, weak cell cycle accumulation in S-phase and later signs of apoptotic cell death. Furthermore, already at sub-cytotoxic concentrations KP46 reduced the migratory potential of osteosarcoma cells and exerted synergistic effects with cisplatin, a standard osteosarcoma chemotherapeutic. Moreover, the gallium compound induced signs of autophagy in osteosarcoma cells. Accordingly, blockade of autophagy by chloroquine but also by the Bcl-2 inhibitor obatoclax increased the cytotoxic activity of KP46 treatment significantly, suggesting autophagy induction as a protective mechanism against KP46. Conclusion Together, our results identify KP46 as a new promising agent to supplement standard chemotherapy and possible future targeted therapy in osteosarcoma.http://link.springer.com/article/10.1186/s13046-017-0527-zOsteosarcomaKP46Anticancer gallium compoundAutophagyObatoclax |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bernd Kubista Thomas Schoefl Lisa Mayr Sushilla van Schoonhoven Petra Heffeter Reinhard Windhager Bernhard K. Keppler Walter Berger |
spellingShingle |
Bernd Kubista Thomas Schoefl Lisa Mayr Sushilla van Schoonhoven Petra Heffeter Reinhard Windhager Bernhard K. Keppler Walter Berger Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition Journal of Experimental & Clinical Cancer Research Osteosarcoma KP46 Anticancer gallium compound Autophagy Obatoclax |
author_facet |
Bernd Kubista Thomas Schoefl Lisa Mayr Sushilla van Schoonhoven Petra Heffeter Reinhard Windhager Bernhard K. Keppler Walter Berger |
author_sort |
Bernd Kubista |
title |
Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition |
title_short |
Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition |
title_full |
Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition |
title_fullStr |
Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition |
title_full_unstemmed |
Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition |
title_sort |
distinct activity of the bone-targeted gallium compound kp46 against osteosarcoma cells - synergism with autophagy inhibition |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2017-04-01 |
description |
Abstract Background Osteosarcoma is the most frequent primary malignant bone tumor. Although survival has distinctly increased due to neoadjuvant chemotherapy in the past, patients with metastatic disease and poor response to chemotherapy still have an adverse prognosis. Hence, development of new therapeutic strategies is still of utmost importance. Methods Anticancer activity of KP46 against osteosarcoma cell models was evaluated as single agent and in combination approaches with chemotherapeutics and Bcl-2 inhibitors using MTT assay. Underlying mechanisms were tested by cell cycle, apoptosis and autophagy assays. Results KP46 exerted exceptional anticancer activity at the nanomolar to low micromolar range, depending on the assay format, against all osteosarcoma cell models with minor but significant differences in IC50 values. KP46 treatment of osteosarcoma cells caused rapid loss of cell adhesion, weak cell cycle accumulation in S-phase and later signs of apoptotic cell death. Furthermore, already at sub-cytotoxic concentrations KP46 reduced the migratory potential of osteosarcoma cells and exerted synergistic effects with cisplatin, a standard osteosarcoma chemotherapeutic. Moreover, the gallium compound induced signs of autophagy in osteosarcoma cells. Accordingly, blockade of autophagy by chloroquine but also by the Bcl-2 inhibitor obatoclax increased the cytotoxic activity of KP46 treatment significantly, suggesting autophagy induction as a protective mechanism against KP46. Conclusion Together, our results identify KP46 as a new promising agent to supplement standard chemotherapy and possible future targeted therapy in osteosarcoma. |
topic |
Osteosarcoma KP46 Anticancer gallium compound Autophagy Obatoclax |
url |
http://link.springer.com/article/10.1186/s13046-017-0527-z |
work_keys_str_mv |
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