Enhancing the Therapeutic Efficacy of Gefitinib in Human Non-Small-Cell Lung Cancer through Drug Combination.

Abstract

The interaction between tumor cells and the tumor microenvironment (TME) significantly influences tumorigenesis, so TME-targeted therapy has attracted widespread attention. We have previously demonstrated that the combination of dipyridamole, bestatin, and dexamethasone (DBD mix, DBDx) is effective against heterogeneous human pancreatic cancer and hepatocellular carcinoma in mouse xenograft models. To further expand the therapeutic potential of this drug combination, herein, we investigated the antitumor efficacy and the underlying mechanism of DBDx and the combination of DBDx and gefitinib in different mouse xenograft models of human non-small-cell lung cancer (NSCLC). Three human cancer cell lines H460, PG, and A431 were used to determine the apoptosis and growth inhibition induced by DBDx, gefitinib, and their combinations. Changes in epidermal growth factor receptor (EGFR) signaling pathway-related proteins were analyzed following treatment using western blotting. In vitro, DBDx strongly inhibited the proliferation of tumor cells, whereas the combined treatment exhibited a significant synergistic effect. Compared with DBDx, the combination treatment further induced apoptosis and downregulated the expression of molecules associated with EGFR signaling pathway. In vivo, compared with DBDx alone, the combination treatment distinctly inhibited tumor growth in mouse xenograft models of human NSCLC. Overall, our results indicate that the combination of DBDx and gefitinib in the treatment of human NSCLC is very promising, which warrants further translational studies.

• Authors: Mengran Zhang, Hao Cai, Yue Du, Yuexuan Wang, Jianhua Gong, Jian Xu, Xiujun Liu
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 18 Issue 3 Pg. 1397-1407 (03 01 2021) ISSN: 1543-8392 [Electronic] United States
• PMID: 33471533 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• Protein Kinase Inhibitors
• ErbB Receptors
• Gefitinib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Cell Cycle
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Combinations
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• ErbB Receptors (metabolism)
• Female
• Gefitinib (pharmacology)
• Humans
• Lung Neoplasms (diet therapy, metabolism)
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Mice