Exploration of potential molecular mechanisms and genotoxicity of anti-cancer drugs using next generation knowledge discovery methods

Abstract

Background & Objectives: Accurate identification of molecular and toxicological functions of potential drug candidates is crucial for drug discovery and development. This may aid in the evaluation of the risks of genotoxicity and carcinogenesis. In addition, in silico characterization of existing and new drugs might offer clues for future investigations and aid in the development of anticancer treatments. Using next-generation knowledge discovery (NGKD) methodology, we endeavored to establish a risk assessment of anticancer drugs for their molecular mechanism(s) and genotoxicity.
 Methods: This study was performed at the Faculty of Applied Medical Sciences, King Abdulaziz University (KAU), Jeddah, Saudi Arabia, in November 2022. Using innovative in silico model systems, we assessed the molecular mechanism of action and toxicity of around 20 distinct substances such as Deguelin, Etoposide, Camptothecin, Cytarabine (Ara-C), Cisplatin, Hydroxyurea, Trichostain A, Antimycin, Colchicine, 2-deoxyglucose, Tunicamycin, Thapsigargin, Vinblastin, Docetaxel, Oxaliplatin, Methotrexate, 5-flurouracil, Bleomycin, Taxol (Paclitaxel), and Apicidin. Using the Ingenuity Pathway Analysis (IPA) knowledge base, the number of targets for each compound was determined in silico. Subsequently, they were examined using Fisher’s exact test and Benjamini Hochberg Multiple Testing Correction (P<0.05) and submitted to core analysis with IPA to decode the biological and toxicological activities differently controlled by these drugs. In addition, a multiple comparison module in IPA was used to compare the core analyses of each molecule. In addition, we obtained the top 100 protein targets of Etoposide, Camptothecin, and Ara-C using SwissTargetPrediction, as well as the key pathways and gene ontologies affected by these drugs and disease associations using the WebGestalt tool.
 Results: We identified distinct toxicological signatures and canonical signaling pathways in tumor cell lines regulated by these 20 anticancer drugs. These signaling pathways included cell death and apoptosis in addition to molecular processes, p53 signaling, and aryl hydrocarbon receptor signaling. The TP53 signaling pathway is utilized by these agents to effectively trigger cell death and apoptosis, and p53 functions as a master regulator in a variety of cellular stress responses, including genotoxic stress.
 Conclusion: Our research has laid the groundwork for the discovery of additional biomarkers that assess both the safety and effectiveness of treatment. Our mechanism based “NGKD” tools have more relevance for the identification of safer therapies and has the potential to lead to the rational screening of drug candidates targeting specific molecular networks and canonical pathways implicated in cancer and genotoxicity. In addition, the combination of protein, microRNA and metabolome profiles may be essential for the development of translatable biomarkers for the safety and efficacy of pharmacotherapeutic agents.Our research has laid the groundwork for the discovery of additional biomarkers that assess both the safety and the effectiveness of a treatment.
 doi: https://doi.org/10.12669/pjms.39.4.7427
 How to cite this: Pushparaj PN, Rasool M, Naseer MI, Gauthaman K. Exploration of potential molecular mechanisms and genotoxicity of anti-cancer drugs using next generation knowledge discovery methods. Pak J Med Sci. 2023;39(4):---------. doi: https://doi.org/10.12669/pjms.39.4.7427
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