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


CONCLUSIONS
Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells.
University of Rostock, Division of Medicine, Department of Hematology/Oncology, Rostock, Germany.
Catrin
C
Schult
Meike
M
Dahlhaus
Sabine
S
Ruck
Mandy
M
Sawitzky
Francesca
F
Amoroso
Sandra
S
Lange
Daniela
D
Etro
Aenne
A
Glass
Georg
G
Fuellen
Sonja
S
Boldt
Olaf
O
Wolkenhauer
Luca Maria
LM
Neri
Mathias
M
Freund
Christian
C
Junghanss
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000473:pathology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D019169:Jurkat Cells; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib; D013601:T-Lymphocytes / Q000473:pathology*
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053179:Caspase 7