Repositioning of Anti-Inflammatory Drugs for the Treatment of Cervical Cancer Sub-Types

Medi Kori; Kazim Yalcin Arga; Adil Mardinoglu; Beste Turanli

doi:10.3389/fphar.2022.884548

Repositioning of Anti-Inflammatory Drugs for the Treatment of Cervical Cancer Sub-Types

Front Pharmacol. 2022 Jun 13:13:884548. doi: 10.3389/fphar.2022.884548. eCollection 2022.

Authors

Medi Kori¹, Kazim Yalcin Arga^{1

2}, Adil Mardinoglu^{3

4}, Beste Turanli¹

Affiliations

¹ Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey.
² Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey.
³ Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden.
⁴ Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom.

Abstract

Cervical cancer is the fourth most commonly diagnosed cancer worldwide and, in almost all cases is caused by infection with highly oncogenic Human Papillomaviruses (HPVs). On the other hand, inflammation is one of the hallmarks of cancer research. Here, we focused on inflammatory proteins that classify cervical cancer patients by considering individual differences between cancer patients in contrast to conventional treatments. We repurposed anti-inflammatory drugs for therapy of HPV-16 and HPV-18 infected groups, separately. In this study, we employed systems biology approaches to unveil the diagnostic and treatment options from a precision medicine perspective by delineating differential inflammation-associated biomarkers associated with carcinogenesis for both subtypes. We performed a meta-analysis of cervical cancer-associated transcriptomic datasets considering subtype differences of samples and identified the differentially expressed genes (DEGs). Using gene signature reversal on HPV-16 and HPV-18, we performed both signature- and network-based drug reversal to identify anti-inflammatory drug candidates against inflammation-associated nodes. The anti-inflammatory drug candidates were evaluated using molecular docking to determine the potential of physical interactions between the anti-inflammatory drug and inflammation-associated nodes as drug targets. We proposed 4 novels anti-inflammatory drugs (AS-601245, betamethasone, narciclasin, and methylprednisolone) for the treatment of HPV-16, 3 novel drugs for the treatment of HPV-18 (daphnetin, phenylbutazone, and tiaprofenoic acid), and 5 novel drugs (aldosterone, BMS-345541, etodolac, hydrocortisone, and prednisolone) for the treatment of both subtypes. We proposed anti-inflammatory drug candidates that have the potential to be therapeutic agents for the prevention and/or treatment of cervical cancer.

Keywords: anti-inflammatory drugs; cervical cancer; drug repurposing; human papillomavirus 16; human papillomavirus 18; inflammation.