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The Multikinase Inhibitor AD80 Induces Mitotic Catastrophe and Autophagy in Pancreatic Cancer Cells

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Autor(es):
Lima, Keli ; de Miranda, Livia Bassani Lins ; Garnique, Anali Del Milagro Bernabe ; de Almeida, Bruna Oliveira ; do Nascimento, Mariane Cristina ; Alcantara, Guilherme Augusto Sousa ; Machado-Santelli, Glaucia Maria ; Rego, Eduardo Magalhaes ; Machado-Neto, Joao Agostinho
Número total de Autores: 9
Tipo de documento: Artigo Científico
Fonte: CANCERS; v. 15, n. 15, p. 14-pg., 2023-08-01.
Resumo

Simple Summary Pancreatic cancer is one of the most lethal human neoplasms, and its therapeutic repertoire remains limited. Advances in understanding the molecular complexity involved in the biology of the disease have paved the way for new therapeutic opportunities. AD80 is a multikinase inhibitor that inhibits S6K as well as RET, RAF, and SRC and displays antineoplastic effects in hematological and solid tumors. In the present study, we report the potential of AD80 as an antineoplastic agent for pancreatic cancer and the cellular and molecular changes induced by the drug. Significant advances in understanding the molecular complexity of the development and progression of pancreatic cancer have been made, but this disease is still considered one of the most lethal human cancers and needs new therapeutic options. In the present study, the antineoplastic effects of AD80, a multikinase inhibitor, were investigated in models of pancreatic cancer. AD80 reduced cell viability and clonogenicity and induced polyploidy in pancreatic cancer cells. At the molecular level, AD80 reduced RPS6 and histone H3 phosphorylation and induced & gamma;H2AX and PARP1 cleavage. Additionally, the drug markedly decreased AURKA phosphorylation and expression. In PANC-1 cells, AD80 strongly induced autophagic flux (consumption of LC3B and SQSTM1/p62). AD80 modulated 32 out of 84 autophagy-related genes and was associated with vacuole organization, macroautophagy, response to starvation, cellular response to nitrogen levels, and cellular response to extracellular stimulus. In 3D pancreatic cancer models, AD80 also effectively reduced growth independent of anchorage and cell viability. In summary, AD80 induces mitotic aberrations, DNA damage, autophagy, and apoptosis in pancreatic cancer cells. Our exploratory study establishes novel targets underlying the antineoplastic activity of the drug and provides insights into the development of therapeutic strategies for this disease. (AU)

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: 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: 22/03316-8 - Investigação dos efeitos do inibidor multiquinase AD80 em neoplasias hematológicas com ativação constitutiva de vias tirosina-quinase
Beneficiário:Lívia Bassani Lins de Miranda
Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 19/25421-5 - Avaliação celular e molecular do silenciamento de ANKHD1 em câncer de mama
Beneficiário:Bruna Oliveira de Almeida
Modalidade de apoio: Bolsas no Brasil - Iniciação Científica