Pirarubicin inhibits multidrug-resistant osteosarcoma cell proliferation through induction of G2/M phase cell cycle arrest.

Abstract

AIM:

Pirarubicin (THP) is recently found to be effective in treating patients with advanced, relapsed or recurrent high-grade osteosarcoma. In this study, the effects of THP on the multidrug-resistant (MDR) osteosarcoma cells were assessed, and the underlying mechanisms for the disruption of cell cycle kinetics by THP were explored.

METHODS:

Human osteosarcoma cell line MG63 and human MDR osteosarcoma cell line MG63/DOX were tested. The cytotoxicity of drugs was examined using a cell proliferation assay with the Cell Counting Kit-8 (CCK-8). The distribution of cells across the cell cycle was determined with flow cytometry. The expression of cell cycle-regulated genes cyclin B1 and Cdc2 (CDK1), and the phosphorylated Cdc2 and Cdc25C was examined using Western blot analyses.

RESULTS:

MG63/DOX cells were highly resistant to doxorubicin (ADM) and gemcitabine (GEM), but were sensitive or lowly resistant to THP, methotrexate (MTX) and cisplatin (DDP). Treatment of MG63/DOX cells with THP (200-1000 ng/mL) inhibited the cell proliferation in time- and concentration-dependent manners. THP (50-500 ng/mL) induced MG63/DOX cell cycle arrest at the G(2)/M phase in time- and concentration-dependent manners. Furthermore, the treatment of MG63/DOX cells with THP (200-1000 ng/mL) downregulated cyclin B1 expression, and decreased the phosphorylated Cdc2 at Thr(161). Conversely, the treatment increased the phosphorylated Cdc2 at Thr(14)/Tyr(15) and Cdc25C at Ser(216), which led to a decrease in Cdc2-cyclin B1 activity.

CONCLUSION:

The cytotoxicity of THP to MG63/DOX cells may be in part due to its ability to arrest cell cycle progression at the G(2)/M phase, which supports the use of THP for managing patients with MDR osteosarcoma.

• Authors: Shui-er Zheng, Sang Xiong, Feng Lin, Guang-lei Qiao, Tao Feng, Zan Shen, Da-liu Min, Chun-ling Zhang, Yang Yao
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 33 Issue 6 Pg. 832-8 (Jun 2012) ISSN: 1745-7254 [Electronic] United States
• PMID: 22580740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyclin B1
• Doxorubicin
• pirarubicin
• CDC2 Protein Kinase
• CDC25C protein, human
• cdc25 Phosphatases

Topics

• Antineoplastic Agents (pharmacology)
• CDC2 Protein Kinase (genetics)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin B1 (genetics)
• Doxorubicin (analogs & derivatives, pharmacology)
• G2 Phase (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Osteosarcoma (drug therapy, genetics)
• cdc25 Phosphatases (genetics)