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

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

• 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