Novel benzoylurea derivative decreases TRPM7 channel function and inhibits cancer cells migration
Xiaoding Zhang,
Rui Zong,
Yu Han,
Xiaoming Li,
Shuangyu Liu,
Yixue Cao,
Nan Jiang,
Pingping Chen,
Haixia Gao
Affiliations
Xiaoding Zhang
Department of Pharmacology, Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Hebei Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China
Rui Zong
Department of Pharmacology, Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Hebei Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China
Yu Han
Department of Pharmacy, Hebei Children’s Hospital, Shijiazhuang, Hebei, China
Xiaoming Li
Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei, China
Shuangyu Liu
Department of Pharmacology, Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Hebei Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China
Yixue Cao
Department of Pharmacology, Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Hebei Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China
Nan Jiang
Department of Pharmacology, Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Hebei Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China
Pingping Chen
The Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
Haixia Gao
Department of Pharmacology, Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Hebei Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China
The transient receptor potential melastatin 7 channel (TRPM7) is a nonselective cation channel highly expressed in some human cancer tissues. TRPM7 is involved in the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cancer cells. Modulation of TRPM7 could be a promising therapeutic strategy for treating cancer; however, efficient and selective pharmacological TRPM7 modulators are lacking. In this study we investigated N- [4- (4, 6-dimethyl- 2-pyrimidinyloxy) − 3- methylphenyl] -N’ - [2 -(dimethylamino)] benzoylurea (SUD), a newly synthesized benzoylurea derivative, for its effects on cancer cell migration and EMT and on functional expression of TRPM7. Our previous studies showed that SUD induces cell cycle arrest and apoptosis of MCF-7 and BGC-823 cells (human breast cancer and gastric cancer cell lines, respectively). Here, we show that SUD significantly decreased the migration of both types of cancer cells. Moreover, SUD decreased vimentin expression and increased E-cadherin expression in both cell types, indicating that EMT is also decreased by SUD. Importantly, SUD potentially reduced the TRPM7-like current in a concentration-dependent manner and decreased TRPM7 expression through the PI3K/Akt signaling pathway. Finally, molecular docking simulations were used to investigate potential SUD binding sites on TRPM7. In summary, our research demonstrated that SUD is an effective TRPM7 inhibitor and a potential agent to suppress the metastasis of breast and gastric cancer by inhibiting TRPM7 expression and function.
