Abstract
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.
Highlights
Osteosarcoma is the most common primary malignant neoplasm of the bone
SJSA-1 was derived from an osteosarcoma of the femur with MDM2 proto-oncogene (MDM2) and GLI family zinc finger 1 (GLI1) gene amplification from a 19 year-old male patient. 143B is a TP53-mutant and is a thymidine kinasenegative osteosarcoma cell line derived from a 13 year-old female
We found that SaOS-2, SJSA-1, and 143B osteosarcoma cell lines have significantly increased myeloid cell leukemia-1 protein (MCL-1) mRNA levels when compared to mesenchymal stem cells (MSC) (Figure 2A)
Summary
Osteosarcoma is the most common primary malignant neoplasm of the bone. It typically occurs in children and young adults, but can affect people of all ages [1]. It is derived from primitive bone-forming mesenchymal cells and frequently arises in the metaphyses of long bones [1, 2]. Clinical outcomes for osteosarcoma patients have not substantially improved in over 30 years. Current osteosarcoma treatments comprise a combination of methotrexate, doxorubicin, and cisplatin (a combination referred to as MAP) and occasionally ifosfamide, to induce tumor necrosis [6]. The degree of necrosis induced in the primary tumor is directly correlated with clinical outcome. Approximately 20% of patients relapse even when a high degree of necrosis has been achieved
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