RESUMO
Three-dimensional (3D) cultures are a valuable platform to study acquired multicellular apoptotic resistance of cancer. We used spheroids of cell lines and actual tumor to study resistance to the proteasome inhibitor bortezomib in mesothelioma, a highly chemoresistant tumor. Spheroids from mesothelioma cell lines acquired resistance to bortezomib by failing to upregulate Noxa, a pro-apoptotic sensitizer BH3-only protein that acts by displacing Bim, a pro-apoptotic Bax/Bak-activator protein. Surprisingly, despite their resistance, spheroids also upregulated Bim and thereby acquired sensitivity to ABT-737, an inhibitor of anti-apoptotic Bcl-2 molecules. Analysis using BH3 profiling confirmed that spheroids acquired a dependence on anti-apoptotic Bcl-2 proteins and were 'primed for death'. We then studied spheroids grown from actual mesothelioma. ABT-737 was active in spheroids grown from those tumors (5/7, â¼70%) with elevated levels of Bim. Using immunocytochemistry of tissue microarrays of 48 mesotheliomas, we found that most (33, 69%) expressed elevated Bim. In conclusion, mesothelioma cells in 3D alter the expression of Bcl-2 molecules, thereby acquiring both apoptotic resistance and sensitivity to Bcl-2 blockade. Mesothelioma tumors ex vivo also show sensitivity to Bcl-2 blockade that may depend on Bim, which is frequently elevated in mesothelioma. Therefore, mesothelioma, a highly resistant tumor, may have an intrinsic sensitivity to Bcl-2 blockade that can be exploited therapeutically.
Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos , Mesotelioma/metabolismo , Mesotelioma/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Humanos , Nitrofenóis/farmacologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Esferoides Celulares/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Células Tumorais CultivadasRESUMO
Annuloaortic ectasia (AAE), in which there is an idiopathic aortic root dilation leading to pure aortic regurgitaion (AR), is a rare disorder and is usually seen as a forme--fruste of Marfan's syndrome. We report a case in which the patient presented with rapid onset of symptoms of heart failure and was being treated for mitral regurgitation due to dilated cardiomyopathy. Postmortem findings revealed an enlarged heart with annuloaortic ectasia.