The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) inhibits metastasis of human osteosarcoma cells
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Loredana Zocchi1, Stephanie C. Wu2, Jie Wu3,4, Ken L. Hayama5 and Claudia A. Benavente1,2,4
1Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA
2Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA
3Department of Biological Chemistry, University of California, Irvine, CA 92697, USA
4Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA
5Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697, USA
Claudia A. Benavente, email: [email protected]
Keywords: osteosarcoma; flavopiridol; metastasis; migration; cancer
Received: March 21, 2018 Accepted: April 09, 2018 Published: May 04, 2018
Osteosarcoma is the most common primary malignant neoplasm of bone and typically occurs in children and young adults. As a highly metastatic malignancy, 15–20% of osteosarcoma patients are diagnosed after the tumor has already metastasized (typically to the lungs), which translates to 5-year survival rates of <40%. Here, we tested the effect of the cyclin-dependent kinase (CDK) inhibitor flavopiridol (alvocidib) in U2OS, SaOS-2, SJSA-1, and 143B osteosarcoma tumor cells in vitro and in vivo. Our results show that flavopiridol can drastically decrease survival in these osteosarcoma cell lines at nanomolar concentrations and induce mitotic catastrophe in p53-null osteosarcomas. We also performed transcriptome analysis (RNA-seq) of flavopiridol-treated osteosarcoma cells, which revealed significant changes in genes coding for proteins involved in cell-cell and cell-matrix adhesions, including cadherin 3 (CDH3) and 4 (CDH4). These transcriptional changes translated to a striking reduction in the ability of osteosarcoma cells to migrate and invade in vitro. Further, in vivo assessment of the effects of flavopiridol on osteosarcoma metastasis resulted in a significant reduction in the number of lung metastases in mice treated with flavopiridol at concentrations that are physiologically tolerable. This study suggests that flavopiridol, likely in combination with other cytotoxic chemotherapeutic agents, may be a promising drug for the treatment of osteosarcoma.
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