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The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy

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Lima, Keli ; Pereira-Martins, Diego Antonio ; Lins de Miranda, Livia Bassani ; Coelho-Silva, Juan Luiz ; Leandro, Giovana da Silva ; Weinhauser, Isabel ; Cavaglieri, Rita de Cassia ; Leal, Aline de Medeiros ; da Silva, Wellington Fernandes ; Alencar de Lima Lange, Ana Paula ; Rodrigues Pereira Velloso, Elvira Deolinda ; Griessinger, Emmanuel ; Hilberink, Jacobien R. ; Ammatuna, Emanuele ; Huls, Gerwin ; Schuringa, Jan Jacob ; Rego, Eduardo Magalhaes ; Machado-Neto, Joao Agostinho
Número total de Autores: 18
Tipo de documento: Artigo Científico
Fonte: BLOOD CANCER JOURNAL; v. 12, n. 11, p. 11-pg., 2022-11-09.
Resumo

The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34(+) cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia. (AU)

Processo FAPESP: 15/09228-0 - Detecção e estudo funcional de Macrofágos Associados a Tumor em um modelo transgênico de leucemia promielocítica aguda.
Beneficiário:Isabel Weinhauser
Modalidade de apoio: Bolsas no Brasil - Doutorado
Processo FAPESP: 20/12842-0 - Impacto da ancestralidade genética no desenvolvimento, características moleculares e desfecho clínico em pacientes adultos com Leucemia Linfoblástica Aguda
Beneficiário:Keli Cristina de Lima
Modalidade de apoio: Bolsas no Brasil - Doutorado
Processo FAPESP: 19/23864-7 - Análise compreensiva de dados genômicos para identificação e validação de novos alvos terapêuticos envolvidos na regulação de citoesqueleto celular em Leucemias agudas
Beneficiário:João Agostinho Machado Neto
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 21/11606-3 - Investigação dos efeitos antineoplásicos de novos inibidores de PIP4K2 e HDAC em neoplasias hematológicas
Beneficiário:João Agostinho Machado Neto
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 17/23117-1 - Avaliação da via TP53/TP73 na enxertia de células de leucemia promielocítica aguda em modelo de xenotransplante
Beneficiário:Diego Antonio Pereira Martins
Modalidade de apoio: Bolsas no Brasil - Doutorado