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Article

The Proteasome Inhibitor Ixazomib Inhibits the Formation and Growth of Pulmonary and Abdominal Osteosarcoma Metastases in Mice

1
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, 3086 Victoria, Australia
2
Department of Anatomic Pathology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, 3010 Victoria, Australia
3
Translational Research and Animal Clinical Trial Study Group (TRACTS), Faculty of Veterinary and Agricultural Sciences, University of Melbourne, 3010 Melbourne, Australia
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(5), 1207; https://doi.org/10.3390/cancers12051207
Received: 24 April 2020 / Revised: 7 May 2020 / Accepted: 8 May 2020 / Published: 11 May 2020
(This article belongs to the Special Issue Rare Childhood Malignancy)
Osteosarcoma is the most common form of primary bone cancer. Over 20% of osteosarcoma patients present with pulmonary metastases at diagnosis, and nearly 70% of these patients fail to respond to treatment. Previous work revealed that human and canine osteosarcoma cell lines are extremely sensitive to the therapeutic proteasome inhibitor bortezomib in vitro. However, bortezomib has proven disappointingly ineffective against solid tumors including sarcomas in animal experiments and clinical trials. Poor tumor penetration has been speculated to account for the inconsistency between in vitro and in vivo responses of solid tumors to bortezomib. Here we show that the second-generation proteasome inhibitor ixazomib, which reportedly has enhanced solid tumor penetration compared to bortezomib, is toxic to human and canine osteosarcoma cells in vitro. We used experimental osteosarcoma metastasis models to compare the efficacies of ixazomib and bortezomib against primary tumors and metastases derived from luciferase-expressing KRIB or 143B human osteosarcoma cell lines in athymic mice. Neither proteasome inhibitor reduced the growth of primary intramuscular KRIB tumors, however both drugs inhibited the growth of established pulmonary metastases created via intravenous inoculation with KRIB cells, which were significantly better vascularized than the primary tumors. Only ixazomib slowed metastases from KRIB primary tumors and inhibited the growth of 143B pulmonary and abdominal metastases, significantly enhancing the survival of mice intravenously injected with 143B cells. Taken together, these results suggest ixazomib exerts better single agent activity against osteosarcoma metastases than bortezomib. These data provide hope that incorporation of ixazomib, or other proteasome inhibitors that penetrate efficiently into solid tumors, into current regimens may improve outcomes for patients diagnosed with metastatic osteosarcoma. View Full-Text
Keywords: osteosarcoma; proteasome inhibitors; bortezomib; ixazomib osteosarcoma; proteasome inhibitors; bortezomib; ixazomib
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MDPI and ACS Style

Harris, M.A.; Miles, M.A.; Shekhar, T.M.; Cerra, C.; Georgy, S.R.; Ryan, S.D.; Cannon, C.M.; Hawkins, C.J. The Proteasome Inhibitor Ixazomib Inhibits the Formation and Growth of Pulmonary and Abdominal Osteosarcoma Metastases in Mice. Cancers 2020, 12, 1207. https://doi.org/10.3390/cancers12051207

AMA Style

Harris MA, Miles MA, Shekhar TM, Cerra C, Georgy SR, Ryan SD, Cannon CM, Hawkins CJ. The Proteasome Inhibitor Ixazomib Inhibits the Formation and Growth of Pulmonary and Abdominal Osteosarcoma Metastases in Mice. Cancers. 2020; 12(5):1207. https://doi.org/10.3390/cancers12051207

Chicago/Turabian Style

Harris, Michael A., Mark A. Miles, Tanmay M. Shekhar, Carmelo Cerra, Smitha R. Georgy, Stewart D. Ryan, Claire M. Cannon, and Christine J. Hawkins 2020. "The Proteasome Inhibitor Ixazomib Inhibits the Formation and Growth of Pulmonary and Abdominal Osteosarcoma Metastases in Mice" Cancers 12, no. 5: 1207. https://doi.org/10.3390/cancers12051207

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