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Article

Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model

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Pharmatest Services Oy, 20520 Turku, Finland
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Aurexel Life Sciences Oy, 21240 Askainen, Finland
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Vincit Oyj, 20500 Turku, Finland
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Nuvisan-ICB GmbH, Therapeutic Oncology Research, 13353 Berlin, Germany
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Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
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Department of Cell Biology and Anatomy, Faculty of Medicine, University of Turku, 20014 Turku, Finland
*
Author to whom correspondence should be addressed.
Academic Editors: Manuel Scimeca, Orazio Schillaci, Elena Bonanno, Nicoletta Urbano and Rita Bonfiglio
Int. J. Mol. Sci. 2021, 22(11), 5570; https://doi.org/10.3390/ijms22115570
Received: 31 March 2021 / Revised: 19 May 2021 / Accepted: 21 May 2021 / Published: 25 May 2021
(This article belongs to the Special Issue Bone Metastasis Challenge: New Ideas and Future Perspectives)
Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor–bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease. View Full-Text
Keywords: multiple myeloma; bortezomib; radium-223; dexamethasone; myeloma bone disease; osteoblast; osteoclast; targeted alpha-therapy; 5TGM1 mouse model; systemic model multiple myeloma; bortezomib; radium-223; dexamethasone; myeloma bone disease; osteoblast; osteoclast; targeted alpha-therapy; 5TGM1 mouse model; systemic model
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MDPI and ACS Style

Suominen, M.I.; Mäki-Jouppila, J.; Huhtinen, A.; Sjöholm, B.; Rissanen, J.P.; Luostarinen, A.; Fagerlund, K.M.; Alhoniemi, E.; Siemeister, G.; Mumberg, D.; Käkönen, S.-M.; Scholz, A. Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model. Int. J. Mol. Sci. 2021, 22, 5570. https://doi.org/10.3390/ijms22115570

AMA Style

Suominen MI, Mäki-Jouppila J, Huhtinen A, Sjöholm B, Rissanen JP, Luostarinen A, Fagerlund KM, Alhoniemi E, Siemeister G, Mumberg D, Käkönen S-M, Scholz A. Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model. International Journal of Molecular Sciences. 2021; 22(11):5570. https://doi.org/10.3390/ijms22115570

Chicago/Turabian Style

Suominen, Mari I., Jenni Mäki-Jouppila, Anna Huhtinen, Birgitta Sjöholm, Jukka P. Rissanen, Anniina Luostarinen, Katja M. Fagerlund, Esa Alhoniemi, Gerhard Siemeister, Dominik Mumberg, Sanna-Maria Käkönen, and Arne Scholz. 2021. "Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model" International Journal of Molecular Sciences 22, no. 11: 5570. https://doi.org/10.3390/ijms22115570

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