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Mustofa,1 Pamungkas Bagus Satriyo,1 Artania Adnin Tri Suma,2 Stephanus Satria Wira Waskitha,3 Tutik Dwi Wahyuningsih,3 Eti Nurwening Sholikhah1 1Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia; 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia; 3Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, 55281, IndonesiaCorrespondence: Mustofa, Department of Pharmacology and Therapy, Faculty of Nursing Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia, Tel/Fax +62 274-545188, Email mustofafkugm@gmail.comObjective: Metastasis causes approximately 90% of cancer-related deaths, including in cervical cancer patients. Uncontrolled cell proliferation, migration, and cancer stemness act as critical events in primary tumor growth and cancer metastasis progression in cervical cancer. Here, we investigated the anti-proliferative, anti-migration, and cancer stemness inhibition activity of N-phenyl pyrazoline derivatives against cervical cancer cells.Methods: The chalcone and phenylhydrazine were used to synthesize the N-phenyl pyrazoline 2/5 (P2 and P5). The MTT, colony formation, and wound healing assays were performed to evaluate the N-phenyl pyrazoline effect in HeLa cells. The N-phenyl pyrazolineâs protein target was predicted using SwissTargetPrediction and AutoDock Vina software. The Western blotting assay was performed to evaluate the target proteins. The public dataset analysis was used to confirm the clinical relevance of target protein in cervical cancer patients.Results: N-phenyl pyrazoline 2 and 5 were successfully synthesized. The N-phenyl pyrazolines 2 and 5 exhibit cytotoxic effect in HeLa cell line with 20.26 μM, 4.708 μM of IC50, respectively. Further study shows that the N-phenyl pyrazoline 5 suppresses the cell proliferation and migration ability of HeLa cell line in a dose-dependent manner. Target prediction and molecular docking reveal that EGFR and ERBB2 protein as the main target of the N-phenyl pyrazoline 5 compound. The N-phenyl pyrazoline 5 suppresses the EGFR expression level but not the total ERK1/2. Public data and GSEA analysis found that the EGFR high expression level is positively associated with poor survival, cancer metastasis-related signaling pathways, and cancer stem cell markers in cervical cancer patients. In addition, the N-phenyl pyrazoline 5 reduces the HeLaâs tumorsphere size and cancer stem cell marker, CD133.Conclusion: N-phenyl pyrazoline 5 suppresses the cell viability, proliferation, migration, and cancer stem cell-like phenotype of cervical cancer cells via EGFR inhibition.Graphical Abstract: Keywords: N-phenyl pyrazoline, cervical cancer, cancer stem cell-like phenotype, EGFR |
