Open Access Highly Accessed Research article

The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells

Catrin Schult1, Meike Dahlhaus1, Sabine Ruck1, Mandy Sawitzky1, Francesca Amoroso12, Sandra Lange1, Daniela Etro2, Aenne Glass3, Georg Fuellen3, Sonja Boldt4, Olaf Wolkenhauer4, Luca Maria Neri2, Mathias Freund1 and Christian Junghanss1*

Author Affiliations

1 University of Rostock, Division of Medicine, Department of Hematology/Oncology, Rostock, Germany

2 University of Ferrara, Section of Human Anatomy, Department of Morphology and Embryology, Ferrara, Italy

3 University of Rostock, Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock, Germany

4 University of Rostock, Department of Computer Science, Systems Biology and Bioinformatics, Rostock, Germany

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BMC Cancer 2010, 10:560  doi:10.1186/1471-2407-10-560

Published: 15 October 2010

Abstract

Background

Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear.

Methods

ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined.

Results

Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect.

Conclusion

Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells.