ABSTRACT
BACKGROUND/AIM: Quinazolinone is a privileged chemical structure employed for targeting various types of cancer. This study aimed to demonstrate the antitumor activity of synthesized 6,7-disubstituted-2-(3-fluorophenyl) quinazolines (HoLu-11 to HoLu-14). MATERIALS AND METHODS: The cytotoxicity was assessed by the sulforhodamine B (SRB) assay. The cell cycle was examined by flow cytometry. The expression levels of cell cycle- and apoptosis-related proteins were estimated by western blotting. A xenograft animal model was used to explore the antitumor effects of HoLu-12. RESULTS: Among four synthetic quinazolinone derivatives, HoLu-12 significantly reduced the viability of oral squamous cell carcinoma (OSCC) cells. HoLu-12 induced G2/M arrest and increased the expression of cyclin B, histone H3 (Ser10) phosphorylation, and cleaved PARP, indicating that HoLu-12 could induce mitotic arrest and then apoptosis. Moreover, the combination of HoLu-12 and 5-fluorouracil (5-FU) displayed synergistic toxic effect on OSCC cells. HoLu-12 significantly inhibited tumor growth in vivo. CONCLUSION: HoLu-12 induces mitotic arrest and leads to apoptosis of OSCC cells. Furthermore, HoLu-12 alone or in combination with 5-FU is a potential therapeutic agent for OSCC.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Quinazolinones/pharmacology , Animals , Antineoplastic Agents/chemistry , Carcinoma, Squamous Cell , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , Flow Cytometry , Fluorouracil/pharmacology , Humans , Mice , Mitosis/drug effects , Mouth Neoplasms , Quinazolinones/chemistry , Xenograft Model Antitumor AssaysABSTRACT
The epidermal growth factor receptor (EGFR) is a validated therapeutic target for triple-negative breast cancer (TNBC). In the present study, we synthesize novel adamantanyl-based thiadiazolyl pyrazoles by introducing the adamantane ring to thiazolopyrazoline. On the basis of loss of cell viability in TNBC cells, 4-(adamantan-1-yl)-2-(3-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)thiazole (APP) was identified as a lead compound. Using a Parzen-Rosenblatt Window classifier, APP was predicted to target the EGFR protein, and the same was confirmed by surface plasmon resonance. Further analysis revealed that APP suppressed the phosphorylation of EGFR at Y992, Y1045, Y1068, Y1086, Y1148, and Y1173 in TNBC cells. APP also inhibited the phosphorylation of ERK at Y204 and of STAT3 at Y705, implying that APP downregulates the activity of EGFR downstream effectors. Small interfering RNA mediated depletion of EGFR expression prevented the effect of APP in BT549 and MDA-MB-231 cells, indicating that APP specifically targets the EGFR. Furthermore, APP modulated the expression of the proteins involved in cell proliferation and survival. In addition, APP altered the expression of epithelial-mesenchymal transition related proteins and suppressed the invasion of TNBC cells. Hence, we report a novel and specific inhibitor of the EGFR signaling cascade.
