Cyclopenta[ b ]indoles as novel antimicrotubule agents with antileukemia activity

Autor(es)

Vicari, Hugo Passos ; Gomes, Ralph da Costa ; Lima, Keli ; Rossini, Nicolas de Oliveira ; Rodrigues Junior, Manoel Trindade ; de Miranda, Livia Bassani Lins ; Dias, Marcio Vinicius Bertacini ; Costa-Lotufo, Leticia Veras ; Coelho, Fernando ; Machado-Neto, Joao Agostinho

• Tipo de documento: Artigo Científico
• Fonte: TOXICOLOGY IN VITRO; v. 99, p. 11-pg., 2024-06-01.

Resumo

Acute leukemias present therapeutic challenges despite advances in treatments. Microtubule inhibitors have played a pivotal role in cancer therapy, inspiring exploration into novel compounds like C2E1 from the cyclopenta[b]indole class. In the present study, we investigated C2E1's potential as a therapeutic agent for acute leukemia at molecular, cellular, and genetic levels. C2E1 demonstrated tubulin depolarization activity, significantly reducing leukemia cell viability. Its impact involved multifaceted mechanisms: inducing apoptosis, arrest of cell cycle progression, and inhibition of clonogenicity and migration in leukemia cells. At a molecular level, C2E1 triggered DNA damage, antiproliferative, and apoptosis markers and altered gene expression related to cytoskeletal regulation, disrupting essential cellular processes crucial for leukemia cell survival and proliferation. These findings highlight C2E1's promise as a potential candidate for novel anti-cancer therapies. Notably, its distinct mode of action from conventional microtubule-targeting drugs suggests the potential to bypass common resistance mechanisms encountered with existing treatments. In summary, C2E1 emerges as a compelling compound with diverse effects on leukemia cells, showcasing promising antineoplastic properties. Its ability to disrupt critical cellular functions selective to leukemia cells positions it as a candidate for future therapeutic development. (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: 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: 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: 21/01460-1 - Investigação do potencial antineoplásico de novos fármacos que modulam a dinâmica de microtúbulos em Leucemia Mieloide Aguda
• Beneficiário: Hugo Passos Vicari
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto