title: Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells.
abstract: Cimetidine, a histamine type-2 receptor antagonist, is known to inhibit the growth of several tumors in human and animals, however the mechanism of action underlying this effect remains largely unknown. Here, in the mice model of 3LL lung tumor, cimetidine showed significant inhibition of tumor growth. However, an in vitro study demonstrated that cimetidine showed no effect on proliferation, survival, migration and invasion of 3LL cells. We found that cimetidine reduced CD11b(+)Gr-1(+) myeloid derived-suppressive cell (MDSC) accumulation in spleen, blood and tumor tissue of tumor-bearing mice. In vitro coculture assay showed that cimetidine reversed MDSC-mediated T-cell suppression, and improved IFN-γ production. Further investigation demonstrated that the NO production and arginase I expression of MDSCs were reduced, and MDSCs prone to apoptosis by cimetidine treatment. However, MDSC differentiation was not affect by cimetidine. Importantly, although histamine H2 receptor was expressed in MDSC surface, histamine could not reverse the proapoptosis of cimetidine. Moreover, famotidine also did not have this capacity. We found that cimetidine could induce Fas and FasL expression in MDSC surface, and sequentially regulate caspase-dependent apoptosis pathway. Thus, these findings revealed a novel mechanism for cimetidine to inhibit tumor via modulation of MDSC apoptosis.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou General Hospital, Fuzhou, Fujian 350000, PR China.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Zheng
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Jinpeng
authors.initials: J
authors.lastname: Jia
authors.forename: Kexing
authors.initials: K
authors.lastname: Fan
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Lai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018827:Carcinoma, Lewis Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002927:Cimetidine / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D022423:Myeloid Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology
chemical_list: D006635:Histamine H2 Antagonists; D002927:Cimetidine