Potency and efficacy of pharmacological PIP4K2 inhibitors in acute lymphoblastic leukemia

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Lima, Keli ; Nogueira, Frederico Lisboa ; Cipelli, Marcella ; Carvalho, Maria Fernanda Lopes ; Pereira-Martins, Diego Antonio ; da Silva, Wellington Fernandes ; Cavaglieri, Rita de Cassia ; Nardinelli, Luciana ; Leal, Aline de Medeiros ; Velloso, Elvira Deolinda Rodrigues Pereira ; Bendit, Israel ; Camara, Niels Olsen Saraiva ; Schuringa, Jan Jacob ; Machado-Neto, Joao Agostinho ; Rego, Eduardo Magalhaes

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmacology; v. 977, p. 11-pg., 2024-06-11.

Resumo

Acute lymphoblastic leukemia (ALL), a complex malignancy, displays varying expression profiles of PIP4K2related genes in adult patients. While PIP4K2A expression is elevated in ALL bone marrow cells compared to healthy bone marrow cells, PIP4K2B is downregulated, and PIP4K2C remains relatively unchanged. Despite the correlation between increased PIP4K2A expression and increased percentage of peripheral blood blasts, clinical outcomes do not strongly correlate with the expression of these genes. Here we investigated the therapeutic potential of three PIP4K2 inhibitors (THZ-P1-2, a131, and CC260) in ALL cell models. THZ-P1-2 emerges as the most effective inhibitor, inducing cell death and mitochondrial damage while reducing cell viability and metabolism significantly. Comparative analyses highlight the superior efficacy of THZ-P1-2 over a131 and CC260. Notably, THZ-P1-2 uniquely disrupts autophagic flux and inhibits the PI3K/AKT/mTOR pathway, indicating a distinct molecular mechanism. In summary, our findings elucidate the differential expression of PIP4K2-related genes in ALL and underscore the potential role of PIP4K2A in disease pathogenesis. The therapeutic promise of THZ-P1-2 in ALL treatment, along with its distinct effects on cell death mechanisms and signaling pathways, enriches our understanding of PIP4K2 ' s involvement in ALL development and offers targeted therapy prospects. (AU)

• 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: 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