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

Author(s)

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

• Document type: Journal article
• Source: Life Sciences; v. 308, p. 9-pg., 2022-09-02.

Abstract

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)

• FAPESP's process: 18/19372-9 - Investigation of the effect of potential Stathmin 1 inhibitors obtained by chemoinformatics on the phenotype of acute leukemias
• Grantee: Jorge Antonio Elias Godoy Carlos
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/24993-0 - Investigation of Stathmin 1 and microtubule instability in phenotype of hematological neoplasms
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/17595-0 - Study of pradimicina-IRD molecular interaction with DNA and its tumor cell mechanism of action
• Grantee: Larissa Costa de Almeida
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/23864-7 - Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute Leukemia
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/11606-3 - Investigation of the antineoplastic effects of novel PIP4K2 and HDAC inhibitors in hematologic malignancies
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds
• Grantee: Leticia Veras Costa Lotufo
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants