结直肠癌是一种高度侵袭性和转移性癌症,临床结果不充分。鉴于组胺和组胺受体在结直肠癌发生中的关键作用,本研究旨在探讨特非那定对大肠癌HCT116细胞的抗癌作用及其机制。
■这里,我们在体外和体内研究了特非那定对HCT116细胞生长和增殖的影响。各种实验技术,如流式细胞术,westernblot,免疫沉淀,荧光素酶分析用于揭示特非那定引发细胞死亡的机制。
■特非那定通过消除组胺H1受体(H1N1)信号传导而显著减弱HCT116细胞的活力。此外,特非那定调节Bax和Bcl-2的平衡,触发细胞质中细胞色素c的放电,从而刺激半胱天冬酶级联和聚(ADP-核糖)聚合酶(PARP)降解。此外,特非那定抑制小鼠双minute-2(Mdm2)表达,而p53表达增加。特非那定通过抑制HCT116细胞中的MEK/ERK和JAK2活化来抑制STAT3磷酸化及其基因产物的表达。此外,用MEK抑制剂U0126治疗,和AG490,一种JAK2抑制剂,ERK1/2和JAK2的磷酸化分别显著减少,导致STAT3下调。同样,特非那定减少了MEK1/2与β-抑制蛋白2的复合物形成。此外,特非那定降低了PKC底物的磷酸化。特非那定给药(10mg/kg)基本上延缓了体内HCT116肿瘤异种移植物的生长。
■特非那定通过抑制STAT3信号诱导HCT116细胞凋亡。总的来说,这项研究支持特非那定作为结直肠癌的重要抗癌疗法。
UNASSIGNED: Colorectal cancer is a highly aggressive and metastatic cancer with inadequate clinical outcomes. Given the crucial role of histamine and histamine receptors in colorectal carcinogenesis, this study aimed at exploring the anticancer effects of terfenadine against colorectal cancer HCT116 cells and elucidate its underlying mechanism.
UNASSIGNED: Herein, we examined the effect of
terfenadine on growth and proliferation of HCT116 cells in vitro and in vivo. Various experimental techniques such as flow cytometry, western blot, immunoprecipitation, luciferase assay were employed to unveil the mechanism of cell death triggered by terfenadine.
UNASSIGNED: Terfenadine markedly attenuated the viability of HCT116 cells by abrogating histamine H1 receptor (H1R) signaling. In addition,
terfenadine modulated the balance of Bax and Bcl-2, triggering cytochrome c discharge in the cytoplasm, thereby stimulating the caspase cascade and poly-(ADP-ribose) polymerase (PARP) degradation. Moreover, terfenadine suppressed murine double minute-2 (Mdm2) expression, whereas p53 expression increased. Terfenadine suppressed STAT3 phosphorylation and expression of its gene products by inhibiting MEK/ERK and JAK2 activation in HCT116 cells. Furthermore, treatment with U0126, a MEK inhibitor, and AG490, a JAK2 inhibitor, dramatically diminished the phosphorylations of ERK1/2 and JAK2, respectively, leading to STAT3 downregulation. Likewise,
terfenadine diminished the complex formation of MEK1/2 with β-arrestin 2. In addition,
terfenadine dwindled the phosphorylation of PKC substrates. Terfenadine administration (10 mg/kg) substantially retarded the growth of HCT116 tumor xenografts in vivo.
UNASSIGNED: Terfenadine induces the apoptosis of HCT116 cells by abrogating STAT3 signaling. Overall, this study supports
terfenadine as a prominent anticancer therapy for colorectal cancer.