Synthetic cyclopenta [b] indoles exhibit antineoplastic activity by targeting microtubule dynamics in acute myeloid leukemia cells

Autor(es):Mostrar menos -

Vicari, Hugo Passos ^[1] ; Lima, Keli ^[1] ; Gomes, Ralph da Costa ^[2] ; Fernandes, Daniara Cristina ^{[3, 2]} ; Lipreri da Silva, Jean Carlos ^[1] ; Rodrigues Junior, Manoel Trindade ^[2] ; Barroso de Oliveira, Aline Silva ^[2] ; dos Santos, Ricardo Nascimento ^[4] ; Andricopulo, Adriano Defini ^[4] ; Coelho, Fernando ^[2] ; Costa-Lotufo, Leticia Veras ^[1] ; Machado-Neto, Joao Agostinho ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Av Prof Lineu Prestes 1524, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Estadual Campinas, Chem Inst, Dept Organ Chem, BR-13083970 Campinas, SP - Brazil

^[3] Inst Fed Educ Ciencia & Tecnol Sao Paulo, BR-15991502 Matao, SP - Brazil

^[4] Univ Sao Paulo, Phys Inst Sao Carlos, BR-13565905 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmacology; v. 894, MAR 5 2021.
• Citações Web of Science: 0

Resumo

Acute promyelocytic leukemia (APL) is associated with PML-RAR alpha oncogene, which is treated using all-trans retinoic acid (ATRA)-based chemotherapy. However, chemoresistance is observed in 20-30% of treated patients and represents a clinical challenge, raising the importance of the development of new therapeutic options. In the present study, the effects of three synthetic cyclopenta{[}b]indoles on the leukemia phenotype were investigated using NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Among the tested synthetic cyclopenta{[}b]indoles, compound 2, which contains a heterocyclic nucleus, was the most active, presenting time-dependent cytotoxic activity in the mu M range in APL cells, without cytotoxicity for normal leukocytes, and was selected for further characterization. Compound 2 significantly decreased clonogenicity, increased apoptosis, and caused cell cycle arrest at S and G(2)/M phases in a drug concentration-dependent manner. Morphological analyses indicated aberrant mitosis and diffuse tubulin staining upon compound 2 exposure, which corroborates cell cycle findings. In the molecular scenario, compound 2 reduced STMN1 expression and activity, and induced PARP1 cleavage and H2AX and CHK2 phosphorylation, and modulated CDKN1A, PMAIP1, GADD45A, and XRCC3 expressions, indicating reduction of cell proliferation, apoptosis, and DNA damage. Moreover, in the in vivo tubulin polymerization assay, NB4 and NB4-R2 cells showed a reduction in the levels of polymerized tubulin upon compound 2 exposure, which indicates tubulin as a target of the drug. Molecular docking supports this hypothesis. Taken together, these data indicated that compound 2 exhibits antileukemic effects through disrupting the microtubule dynamics, identifying a possible novel potential antineoplastic agent for the treatment of ATRA-resistant APL. (AU)

• Processo FAPESP: 19/01700-2 - Investigação funcional de Stathmin 1 na proliferação, diferenciação e apoptose em modelo de leucemia promielocítica aguda
• Beneficiário: Hugo Passos Vicari
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• 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: 15/17177-6 - Abordagem integrada na prospecção sustentável de produtos naturais marinhos: da diversidade a substâncias anticâncer
• Beneficiário: Leticia Veras Costa Lotufo
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático
• Processo FAPESP: 17/24993-0 - Investigação da participação de Stathmin 1 e da instabilidade dos microtúbulos no fenótipo de neoplasias hematológicas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular