CXCR2-IN-3 is a CXCR2 inhibitor with an IC50 of 11.37 μM. It inhibits the CXCR2-Ca2+ signaling pathway, thereby blocking autophagic flux and promoting ROS-mediated apoptosis. Additionally, CXCR2-IN-3 suppresses the CXCR2-NLRP3 canonical pathway, reducing the expression of tumor-promoting markers. This compound induces autophagy-dependent cell death in polyploid giant cancer cells (PGCC) and is applicable in studies related to oral squamous cell carcinoma (OSCC).

[125I]-IL8-CXCR2:11.37 μM

CXCR2-IN-3 (compound 5) exhibits potent ROS scavenging activity in RAW 264.7 macrophages. When combined with 5-Fluorouracil, it demonstrates significant cytotoxicity with an LD50 of 48.00 μM in CAL27 cells. At concentrations of 25-100 μM, CXCR2-IN-3 inhibits CAL27 cell migration and reduces their clonogenic capacity. The compound also decreases IL-8 expression in both CAL27 cells and LPS-stimulated CAL27 cells and lowers Ca2+ levels in CAL27 cells. CXCR2-IN-3 (10-50 μM) induces autophagy in a dose-dependent manner, evidenced by increased LC3 puncta formation in CAL27 cells. Additionally, CXCR2-IN-3 reduces Rapamycin-induced autophagosome-lysosome fusion. The compound displays autophagy flux inhibitory effects, promoting an anti-inflammatory response in oral cancer cells by downregulating the classic CXCR2-NLRP3 signaling pathway. CXCR2-IN-3 (5 μM, 50 μM; 21 days, 24 h) can activate oral cancer cells and enhance the chemotherapy sensitivity of CAL27 cells. At 5-50 μM over 24-72 h, CXCR2-IN-3 induces autophagy-dependent cell death in PGCCs (cisplatin-resistant oral cancer cells) and triggers autophagy-mediated apoptotic cell death in CAL27 cells by reducing autophagic flux.