Sorafenib induces apoptosis and autophagy in prostate cancer cells in vitro.
The multiple tyrosine kinase inhibitor sorafenib has recently demonstrated clinical effects in patients with androgen-independent prostate cancer. These observations provided the rational for investigating the anti-tumoral properties of this compound on prostate cancer cell lines at the molecular level. Two hormone refractory (PC3 and DU145) and one hormone responsive cell line (22Rv1) were used. By use of a panel of cell biology techniques such as immunoblotting, flow cytometry and immunocytochemistry, effects on the MAPK pathway and induction of apoptosis and autophagy were evaluated. We demonstrate that sorafenib reduced cell viability in a dose-dependent manner, induced apoptosis and inactivated the MAPK pathway. Moreover, we show for the first time, that sorafenib treatment of prostate cancer cells also induces cellular autophagy. This feature is in accordance with the anticancer potential of sorafenib and adds another important effector mechanism of this compound. These observations may open potentially interesting treatment combinations that may augment the effect of sorafenib, either by drugs that promote autophagy such as the rapalogues, or by combining sorafenib with compounds that specifically inhibit the autophagic process.
Ullén
Anders
A
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, 17176 Stockholm, Sweden. anders.ullen@karolinska.se
Farnebo
Marianne
M
Thyrell
Lena
L
Mahmoudi
Salah
S
Kharaziha
Pedram
P
Lennartsson
Lena
L
Grandér
Dan
D
Panaretakis
Theoharis
T
Nilsson
Sten
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D019254:Genes, bcl-2 / Q000502:physiology; D006801:Humans; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases