AD80, a multikinase inhibitor, as a potential drug candidate for colorectal cancer therapy

Autor(es)

de Almeida, Larissa Costa ; Carlos, Jorge Antonio Elias Godoy ; Rezende-Teixeira, Paula ; Machado-Neto, Joao Agosrinho ; Costa-Lotufo, Leticia Veras

• Tipo de documento: Artigo Científico
• Fonte: Life Sciences; v. 308, p. 9-pg., 2022-09-02.

Resumo

Aims: Colorectal cancer (CRC) is a very heterogeneous disease. One of its hallmarks is the dysregulation of protein kinases, which leads to molecular events related to carcinogenesis. Hence, kinase inhibitors have been developed and are a new strategy with promising potential for CRC therapy. This study aims to explore AD80, a multikinase inhibitor, as a drug option for CRC, with evaluation of the PI3K/AKT/mTOR and MAPK (ERK1/2) status of CRC cells' panel and the cytotoxicity of AD80 in those cells, as well as in normal colon cells. Main methods: Cellular and molecular mechanisms, such as clonogenicity, cell cycle, morphology, protein and mRNA expression, were investigated in CRC cells after AD80 exposure. Key findings: Results show that PI3K/AKT/mTOR and MAPK signaling pathways are upregulated in CRC cellular models, with increased phosphorylation of mTOR, P70S6K, S6RP, 4EBP1, and ERK1/2. Hence, AD80 selectively reduces cell viability of CRC cells. Therefore, the antitumor mechanisms of AD80, such as clonogenicity inhibition (reduction of colony number and size), G(2)/M arrest (increased G(2)/M population, and CDKN1B mRNA expression), DNA damage (increased H2AX and ERK1/2 phosphorylation, and CDKN1A and GADD45A mRNA expression), apoptosis (increased PARP1 cleavage, and BAX, PMAIP1, BBC3 mRNA expression) and inhibition of S6RP phosphorylation were validated in CRC model. Significance: Our findings reinforce kinases as promising cancer therapeutic targets for the treatment of colorectal cancer, suggesting AD80 as a drug candidate. (AU)

• Processo FAPESP: 18/19372-9 - Investigação do efeito de potenciais inibidores de Stathmin 1 obtidos através de quimioinformática no fenótipo das leucemias agudas
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• Modalidade de apoio: Bolsas no Brasil - Mestrado
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• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
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• Modalidade de apoio: Auxílio à Pesquisa - Regular
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• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático