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Unveiling the Intricacies of Monoamine Oxidase-A (MAO-A) Inhibition in Colorectal Cancer: Computational Systems
Sanaa K Bardaweel1, Husam Al-Salamat1, Rima Hajjo2,3,4
1Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman - 11942, Jordan.
Abstract:
Colorectal cancer (CRC) remains a significant health burden globally, necessitating a deeper understanding of its molecular intricacies for effective therapeutic interventions. Elevated monoamine oxidase-A (MAO-A) expression has been consistently observed in CRC tissues, correlating with advanced disease stages and a poorer prognosis. This research explores the systems biology effects of MAO-A inhibition with small molecule inhibitor clorgyline regarding CRC. The applied systems biology approach starts with a chemocentric informatics approach to derive high-confidence hypotheses regarding the antiproliferative effects of MAO-A inhibitors and ends with experimental validation. Our computational results emphasized the anticancer effects of MAO-A inhibition and the chemogenomics similarities between clorgyline and structurally diverse groups of apoptosis inducers in addition to highlighting apoptotic, DNA-damage, and microRNAs in cancer pathways. Experimental validation results revealed that MAO inhibition results in antiproliferative antimigratory activities in addition to synergistic effects with doxorubicin. Moreover, the results demonstrated a putative role of MAO-A inhibition in commencing CRC cellular death by potentially mediating the induction of apoptosis.
Insights
Monoamine oxidase-A (MAO-A) inhibition shows promise for colorectal cancer (CRC) treatment. Targeting MAO-A with clorgyline demonstrated anticancer effects, including antiproliferative and pro-apoptotic activities, suggesting a new therapeutic avenue.
Area of Science:
- Molecular biology
- Systems biology
- Oncology
Background:
- Colorectal cancer (CRC) presents a global health challenge.
- Elevated monoamine oxidase-A (MAO-A) expression is linked to advanced CRC and poor prognosis.
Purpose of the Study:
- To investigate the systems biology effects of MAO-A inhibition using the small molecule inhibitor clorgyline in colorectal cancer.
- To explore the antiproliferative mechanisms of MAO-A inhibitors in CRC.
Main Methods:
- A systems biology approach integrating chemocentric informatics and experimental validation.
- Computational analysis to identify hypotheses regarding MAO-A inhibitor effects.
- In vitro experimental validation of MAO-A inhibition's impact on CRC cells.
Main Results:
- MAO-A inhibition demonstrated significant anticancer effects, including antiproliferative and antimigratory activities.
- Computational findings highlighted chemogenomic similarities between clorgyline and apoptosis inducers, implicating apoptotic and DNA-damage pathways.
- Experimental validation confirmed MAO-A inhibition's role in inducing CRC cell death, potentially via apoptosis, and showed synergistic effects with doxorubicin.
Conclusions:
- MAO-A inhibition, exemplified by clorgyline, exhibits potent anticancer properties against colorectal cancer.
- MAO-A inhibition may serve as a therapeutic strategy for CRC by inducing apoptosis and enhancing chemotherapy efficacy.
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