Antiproliferative Potential of Linagliptin-Rivaroxaban Mixture in Cervical Cancer: Mechanistic Insights into Targeting Mutant MAPK, RAS kinase Signal Protein

Yousif, Buthaina Jasim; Abd Alwahab, Doaa Hassan; Mohammed, Haneen A.; Yasin, Youssef Shakuri; Jumaa, Azal Hamoody

doi:10.31557/APJCP.2025.26.8.3053

Antiproliferative Potential of Linagliptin-Rivaroxaban Mixture in Cervical Cancer: Mechanistic Insights into Targeting Mutant MAPK, RAS kinase Signal Protein

Document Type : Research Articles

Authors

¹ College of Education for Pure Sciences, Tikrit University, Iraq.

² College of Pharmacy, University of Kirkuk, Iraq.

³ Bilad Alrafidain University, Iraq.

⁴ Iraqi National Cancer Research Center, University of Baghdad, Baghdad, Iraq.

10.31557/APJCP.2025.26.8.3053

Abstract

Background: Repositioning existing marketed drugs represents a viable strategy for identifying new anticancer agents. This study employed an approach that combined these drugs and examined their molecular mechanisms of action against cancer. Objective: This study evaluated the anticancer properties of the linagliptin-rivaroxaban mixture and its molecular anticancer mechanism by screening its ability to target the mutant MAPK-RAS kinase signal proteins. Methods: Following 24 and 72 hours of incubation, HeLa and human-derived adipose tissue (NHF) cell lines were utilized to investigate the anticancer and safety properties of a linagliptin-rivaroxaban mixture and cisplatin at concentrations between 0.1 and 1,000 µg/ml. A combination and selectivity index study assessed the potential synergistic effects between mixture ingredients and selective toxicity. Computational molecular docking simulations were employed to investigate the binding affinity of linagliptin and rivaroxaban to various mutant kinase signal proteins within the MAPK-RAS kinase pathway. Results: The study results indicated that the combination of linagliptin and rivaroxaban significantly suppressed the growth of cervical cancer cells compared to the inhibitory effects of cisplatin, linagliptin, and rivaroxaban individually. Furthermore, the mixture cytotoxicity on the NHF cell line was significantly lower than that of cisplatin. The interaction between linagliptin and rivaroxaban exhibited synergistic cytotoxicity, as evidenced by the combination index score. The mixture exhibited selective cytotoxicity against cancer cells, suggesting a favorable toxicity index score. The outcomes of the molecular docking pilot study of diverse mutant MAPK-RAS kinase signal proteins with the mixture’s ingredients are indicated. Linagliptin and rivaroxaban’s best interactions were with mutant P38 MAPK and RAS kinase signal proteins, with docking scores of -7.9 kcal/mol and -8.7 kcal/mol, respectively. Conclusion: Regarding the study findings and the established pharmacokinetic and safety profiles of mixture drugs. The linagliptin-rivaroxaban mixture offers an attractive and safer alternative for cervical cancer treatment.

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