A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells

• Published in: Drug design, development and therapy Vol. 16; pp. 2325 - 2339
• Main Authors: Mustofa, Satriyo, Pamungkas Bagus, Suma, Artania Adnin Tri, Waskitha, Stephanus Satria Wira, Wahyuningsih, Tutik Dwi, Sholikhah, Eti Nurwening
• Format: Journal Article
• Language: English
• Published: Macclesfield Dove Medical Press Limited 31.07.2022; Taylor & Francis Ltd; Dove; Dove Medical Press
• Subjects: Analysis; Breast cancer; Cancer; Cancer cells; cancer stem cell-like phenotype; Cancer therapies; Cell growth; Cell migration; Cell proliferation; Cell size; Cell viability; Cervical cancer; Cervix; Cytotoxicity; Development and progression; egfr; Epidermal growth factor receptors; ErbB-2 protein; Genetic aspects; Genotype & phenotype; Hydrazine; Ligands; Markers; Medical prognosis; Membranes; Metastases; Metastasis; Molecular docking; n-phenyl pyrazoline; Original Research; Patients; Phenotypes; Prevention; Proteins; Stem cells; Synthesis; Tumors; Western blotting; Womens health; Wound healing; Indonesia; United States > US
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S350913

Objective: 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 pyrazoline's 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 [micro]M, 4.708 [micro]M of [IC.sub.50], 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 HeLa's 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. Keywords: N-phenyl pyrazoline, cervical cancer, cancer stem cell-like phenotype, EGFR