巴泽多昔芬作为一种新型 GP130 抑制剂在结肠癌治疗中的应用。
Bazedoxifene as a novel GP130 inhibitor for Colon Cancer therapy.
机构信息
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD, 21201, USA.
出版信息
J Exp Clin Cancer Res. 2019 Feb 8;38(1):63. doi: 10.1186/s13046-019-1072-8.
BACKGROUND
Interleukin-11 (IL-11), a dominant IL-6 family cytokine, is involved in tumorigenesis, tumor progression and differentiation in colon cancer cells. IL-11 signaling has been recently identified as a potential therapeutic target in colon cancer. Bazedoxifene, a third- generation selective estrogen modulator approved by the Food and Drug Administration (FDA), is a novel inhibitor of IL-11/GP130 signaling discovered by docking modeling.
METHODS
In this study, the inhibition efficacy of bazedoxifene in colon cancer cells and its potential mechanism were investigated in vitro and in vivo by using MTT cell viability assay, BrdU cell proliferation assay, colony formation assay, wound-healing/cell migration assay, immunofluorescence, western blot assay and the mouse xenograft tumor model.
RESULTS
Bazedoxifene inhibits phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and its nuclear translocation induced by IL-11 in colon cancer cells. It also inhibits p-STAT3 induced by IL-6 and IL-11 but not by OSM or STAT1 phosphorylation induced by INF-γ in human colon cancer cells. In addition, bazedoxifene can significantly inhibit phosphorylation of AKT and STAT3 downstream targets. Furthermore, bazedoxifene alone or together with oxaliplatin can significantly induce apoptosis, inhibit cell viability, cell colony formation and cell migration in colon cancer cells. Knock-down of IL-11R can reduce the sensitivity of colon cancer cells to bazedoxifene. IL-11 can reduce the efficacy of oxaliplatin-mediated inhibition of cell viability. Consistent with in vitro findings, bazedoxifene alone also attenuated HCT-15 xenograft tumor burden and reduced p-STAT3, p-AKT and p-ERK in vivo. Its combination with oxaliplatin attenuated DLD-1 xenograft tumor burden and reduced p-STAT3 in vivo.
CONCLUSIONS
Taken together, these results support bazedoxifene as a novel and effective therapeutic agent targeting IL-11/GP130 signaling for human colorectal cancer therapy.
背景
白细胞介素-11（IL-11）是一种主要的白细胞介素 6 家族细胞因子，参与结肠癌的肿瘤发生、肿瘤进展和分化。IL-11 信号已被最近确定为结肠癌的一个潜在治疗靶点。被食品和药物管理局（FDA）批准的第三代选择性雌激素调节剂巴多昔芬是一种新的 IL-11/GP130 信号抑制剂，是通过对接建模发现的。
方法
在这项研究中，通过 MTT 细胞活力测定、BrdU 细胞增殖测定、集落形成测定、划痕愈合/细胞迁移测定、免疫荧光、Western blot 测定和小鼠异种移植肿瘤模型，在体外和体内研究了巴多昔芬对结肠癌细胞的抑制作用及其潜在机制。
结果
巴多昔芬抑制 IL-11 诱导的结肠癌细胞中信号转导和转录激活因子 3（p-STAT3）的磷酸化及其核易位。它还抑制由 IL-6 和 IL-11 诱导的 p-STAT3，但不抑制由 INF-γ诱导的 OSM 或 STAT1 磷酸化。此外，巴多昔芬可显著抑制 AKT 和 STAT3 下游靶标的磷酸化。此外，巴多昔芬单独或与奥沙利铂联合使用可显著诱导结肠癌细胞凋亡，抑制细胞活力、细胞集落形成和细胞迁移。IL-11R 的敲低可降低结肠癌细胞对巴多昔芬的敏感性。IL-11 可降低奥沙利铂抑制细胞活力的疗效。与体外研究结果一致，巴多昔芬单独使用也可减轻 HCT-15 异种移植肿瘤负担，并降低体内 p-STAT3、p-AKT 和 p-ERK。它与奥沙利铂联合使用可减轻 DLD-1 异种移植肿瘤负担，并降低体内 p-STAT3。
结论
综上所述，这些结果支持巴多昔芬作为一种新型有效的治疗剂，针对人类结直肠癌治疗的 IL-11/GP130 信号。
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