Expressão de miRNAs apoptóticos por células da linhagem de leucemia linfocítica crônica MEC-1 após tratamento com Ibrutinib (pci-32765) e Tricostatina A
Arquivos
Data
2023-07-10
Autores
Alves, Brenda Iwakura 
Orientadores
Popi, Ana Flavia
Tipo
Trabalho de conclusão de curso
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A Leucemia linfocítica crônica (LLC) é caracterizada pelo acúmulo de células
B CD5+ nos órgãos linfóides e no sangue periférico. A incidência é alta em pessoas
acima de 50 anos e seu prognóstico é bastante diverso, afetando também o
tratamento. Diversas terapias estão em uso atualmente, porém, em alguns casos,
pode ocorrer resistência e recidiva da doença, havendo a necessidade de uma
busca por novas alternativas. Vários miRNAs, que tem como função regular os
RNAs mensageiros (RNAm), já foram reportados com expressão anormal em vários
tipos de câncer, incluindo na LLC, podendo atuar no desfecho da doença. A
diversidade de mutações cromossômicas existentes nos pacientes com LLC são a
principal causa da alteração nos miRNAs e consequente efeito no prognóstico. Uma
classe de droga bastante utilizada são os inibidores da Tirosina Quinase de Bruton
(BTK), como o Ibrutinib (IB), que induzem a apoptose celular pela diminuição da
ativação celular, entretanto é grande a probabilidade de resistência devido a uma
mutação que pode ocorrer na enzima. Outra classe de droga promissora que está
sendo estudada são os inibidores de Histonas Desacetilases (HDAC), como a
Tricostatina A (TSA), que podem induzir a apoptose através da inibição da repressão
da transcrição gênica feita pelas HDACs, que estão com níveis elevados na LLC.
Desta forma, esse projeto visou observar a eficácia desses dois tratamentos na
modulação dos miRNAs apoptóticos nas células da linhagem MEC-1, derivadas da
LLC. Foi concluído que devido a resistência do IB, a presença do TSA aprimorou a
eficácia pró-apoptótica dessas drogas, apesar da necessidade de uma outra
investigação de diferentes miRNAs para confirmar as vias efetoras desses fármacos
na LLC.
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B cells in lymphoid organs and peripheral blood. The incidence is higher in people over 50 years of age and its prognosis is quite diverse, also affecting treatment. Several therapies are currently in use however, in some cases, there may be resistance and disease relapsing, which demands a search for new treatment alternatives. Several miRNAs, which have the function of regulating messenger RNAs (mRNA), have already been reported with abnormal expression in several types of cancer, including CLL, and may act in the outcome of the disease. The diversity of chromosomal mutations existing in patients with CLL is the main cause of changes in miRNAs and its consequent effect on prognosis. A widely used class of drug is Bruton's Tyrosine Kinase (BTK) inhibitors, such as Ibrutinib (PCI-32765), which induce cell apoptosis by decreasing cell activation. However, there is a high probability of resistance due to a mutation that can occur in the enzyme. Another promising drug class being studied is Histone Deacetylase (HDAC) inhibitors such as Trichostatin A (TSA), which can induce apoptosis by inhibiting the repression of gene transcription made by HDACs, which are at high levels in LLC. Therefore, this project aims to observe the effectiveness of these two treatments in the modulation of apoptotic miRNAs in MEC-1 lineage, derived from CLL. It was concluded that due to IB resistance, the presence of TSA enhanced the pro-apoptotic efficacy of these drugs, despite the need for further investigation of different miRNAs to confirm the effector pathways of these treatments in CLL.
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B cells in lymphoid organs and peripheral blood. The incidence is higher in people over 50 years of age and its prognosis is quite diverse, also affecting treatment. Several therapies are currently in use however, in some cases, there may be resistance and disease relapsing, which demands a search for new treatment alternatives. Several miRNAs, which have the function of regulating messenger RNAs (mRNA), have already been reported with abnormal expression in several types of cancer, including CLL, and may act in the outcome of the disease. The diversity of chromosomal mutations existing in patients with CLL is the main cause of changes in miRNAs and its consequent effect on prognosis. A widely used class of drug is Bruton's Tyrosine Kinase (BTK) inhibitors, such as Ibrutinib (PCI-32765), which induce cell apoptosis by decreasing cell activation. However, there is a high probability of resistance due to a mutation that can occur in the enzyme. Another promising drug class being studied is Histone Deacetylase (HDAC) inhibitors such as Trichostatin A (TSA), which can induce apoptosis by inhibiting the repression of gene transcription made by HDACs, which are at high levels in LLC. Therefore, this project aims to observe the effectiveness of these two treatments in the modulation of apoptotic miRNAs in MEC-1 lineage, derived from CLL. It was concluded that due to IB resistance, the presence of TSA enhanced the pro-apoptotic efficacy of these drugs, despite the need for further investigation of different miRNAs to confirm the effector pathways of these treatments in CLL.
Descrição
Citação
ALVES, Brenda Iwakura. Expressão de miRNAs apoptóticos por células da linhagem de leucemia linfocítica crônica MEC-1 após tratamento com Ibrutinib (pci-32765) e Tricostatina A. 2023. 25 f. Trabalho de conclusão de curso (Graduação em Biomedicina) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP). São Paulo, 2023.