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Published on: September 30, 2016
AD80, a multikinase inhibitor, as a potential drug candidate for colorectal cancer therapy
Larissa Costa de Almeida1, Jorge Antonio Elias Godoy Carlos1, Paula Rezende-Teixeira1
1Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
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), G2/M arrest (increased G2/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.
Insights
AD80, a multikinase inhibitor, effectively targets dysregulated PI3K/AKT/mTOR and MAPK pathways in colorectal cancer (CRC) cells. This study validates AD80
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Colorectal cancer (CRC) is a heterogeneous disease characterized by protein kinase dysregulation.
- Kinase inhibitors represent a promising therapeutic strategy for CRC.
- Aberrant PI3K/AKT/mTOR and MAPK signaling pathways are implicated in CRC carcinogenesis.
Purpose of the Study:
- To investigate AD80, a multikinase inhibitor, as a potential therapeutic agent for CRC.
- To evaluate the impact of AD80 on PI3K/AKT/mTOR and MAPK (ERK1/2) signaling in CRC cells.
- To assess the cytotoxicity of AD80 in both CRC and normal colon cells.
Main Methods:
- Investigated cellular and molecular mechanisms including clonogenicity, cell cycle, morphology, and protein/mRNA expression in CRC cells.
- Exposed CRC cells to AD80 and analyzed its effects on key signaling pathways.
- Assessed AD80's cytotoxicity in a panel of CRC cells and normal colon cells.
Main Results:
- PI3K/AKT/mTOR and MAPK pathways were found to be upregulated in CRC models, with increased phosphorylation of key proteins.
- AD80 selectively reduced CRC cell viability and inhibited clonogenicity.
- AD80 induced G2/M arrest, DNA damage, and apoptosis, while inhibiting S6RP phosphorylation in CRC cells.
Conclusions:
- Kinases are validated as promising therapeutic targets for colorectal cancer treatment.
- AD80 demonstrates significant potential as a drug candidate for CRC therapy.
- The findings support the continued development of kinase inhibitors for effective CRC treatment.
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