Efeitos contraditórios e paradoxais do Imatinib em duas linhas celulares de cancro da próstata hormono-resistente

Os estadios mais avançados do cancro da próstata caracterizam-se pela aquisição de um fenótipo hormono-resistente, o que tem subjacente a ineficácia das terapias clássicas de ablação de androgénios. O Imatinib mesylate é um agente quimioterapêutico que inibe a actividade tirosina cinase do receptor c-KIT, e que tem vindo a ser usado com sucesso no tratamento de leucemias e tumores sólidos. Contudo, a sua aplicação no cancro da próstata hormono resistente tem mostrado efeitos pouco significativos. Neste trabalho, publicado recentemente no jornal The Prostate, uma equipa de investigação do Centro de Investigação em Ciências da Saúde-Universidade da Beira Interior (CICS-UBI) demonstrou os efeitos contraditórios do Imatinib em duas linhas celulares de cancro da próstata hormono-resistente (HRPC). Além disso, paradoxalmente, o Imatinib induziu o aumento de viabilidade e inibiu a apoptose das células PC3. A resposta diferencial do Imatinib nas células DU145 e PC3 parece estar associada a uma expressão diferencial das diferentes isoformas do c-KIT. Os resultados obtidos poderão ainda contribuir para compreender a ineficácia do Imatinib como opção terapêutica no HRPC.

Autores e Afiliações:

Henrique J Cardoso, Cátia V Vaz, Sara Correia, Marília I Figueira MI, Ricardo Marques, Cláudio J Maia, Sílvia Socorro

CICS-UBI, Health Sciences Research Center, University of Beira Interior, Covilhã, Portugal

Abstract:

BACKGROUND. Imatinib mesylate is a chemotherapeutic drug that inhibits the tyrosine kinase activity of c-KIT and has been successfully used to treat leukemias and some solid tumors. However, its application for treatment of hormone-refractory prostate cancer (HRPC) has shown modest effectiveness and did not follow the outcomes in cultured cells or animal models. Moreover, the molecular pathways by which imatinib induces cytotoxicity in prostate cancer cells are poorly characterized.

METHODS. Two cell line models of HRPC (DU145 and PC3) were exposed to 20 µM of imatinib for 6 to 72 h. MTS assay was used to assess cell viability during the course of experiment. Gene expression analysis of c-KIT, cell-cycle and apoptosis regulators, and angiogenic factors was determined by means of real-time PCR, Western Blot and/or immunocytochemistry. The enzymatic activity of the apoptosis effector, caspase-3 was determined by a colorimetric assay.

RESULTS. Imatinib significantly decreased the viability of DU145 cells but paradoxically augmented the viability of PC3 cells. DU145 cells displayed diminished expression of anti-apoptotic Bcl-2 protein and augmented levels of caspase-8 and caspase-9, as well as, increased enzymatic activity of caspase-3 in response to imatinib. No differences existed on the expression levels of apoptosis-related proteins in PC3 cells treated with imatinib, though the activity of caspase-3 was decreased. The mRNA levels of angiogenic factor VEGF were decreased in DU145-treated cells, whereas an opposite effect was seen in PC3. In addition, it was shown that DU145 and PC3 cells present a differential expression of c-KIT protein variants.

CONCLUSIONS. DU145 and PC3 cells displayed a contradictory behavior in response to imatinib, which was underpinned by a distinct expression pattern (or activity) of target regulators of cell-cycle, apoptosis and angiogenesis. The paradoxical effect of imatinib in PC3 cells may be related with the differential expression of c-KIT protein variants. Moreover, the present findings helped to understand the discrepancies in the efficacy of imatinib as therapeutic option in HRPC.

Revista: The Prostate

Link: http://onlinelibrary.wiley.com/doi/10.1002/pros.22976/abstract