Molecular targeting of the oncoprotein PLK1 in pediatric acute myeloid leukemia: RO3280, a novel PLK1 inhibitor, induces apoptosis in leukemia cells.

Abstract

Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined.

• Authors: Na-Na Wang, Zhi-Heng Li, He Zhao, Yan-Fang Tao, Li-Xiao Xu, Jun Lu, Lan Cao, Xiao-Juan Du, Li-Chao Sun, Wen-Li Zhao, Pei-Fang Xiao, Fang Fang, Guang-Hao Su, Yan-Hong Li, Gang Li, Yi-Ping Li, Yun-Yun Xu, Hui-Ting Zhou, Yi Wu, Mei-Fang Jin, Lin Liu, Jian Ni, Jian Wang, Shao-Yan Hu, Xue-Ming Zhu, Xing Feng, Jian Pan
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 16 Issue 1 Pg. 1266-92 (Jan 07 2015) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 25574601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Azepines
• Cell Cycle Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pyrimidines
• RO3280
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Apoptosis (drug effects)
• Azepines (chemistry, toxicity)
• Cell Cycle Checkpoints (drug effects)
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Child
• Child, Preschool
• Cluster Analysis
• DNA Fragmentation (drug effects)
• Down-Regulation (drug effects)
• Female
• HL-60 Cells
• Humans
• K562 Cells
• Kaplan-Meier Estimate
• Leukemia, Myeloid, Acute (metabolism, mortality, pathology)
• Male
• Protein Kinase Inhibitors (toxicity)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Pyrimidines (chemistry, toxicity)
• Tumor Cells, Cultured
• Up-Regulation (drug effects)