Signal transducer and activator of transcription 3 inhibition alleviates resistance to BRAF inhibition in anaplastic thyroid cancer
INVESTIGATIONAL NEW DRUGS
Authors: Wang, Ying; Hu, Zhigang; Ma, Weiyuan; Niu, Yong; Su, Jingwei; Zhang, Lingxiang; Zhao, Pengxin
Abstract
Anaplastic thyroid cancer (ATC) is a rare type of thyroid cancer (TC) with no effective therapeutic strategy. Although surgery, chemotherapy and radiation are all available for ATC treatment, the median survival for ATC patients is less than 6 months. In this study, we aimed to study on resistant mechanisms to B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor and identify effective combinational therapy for ATC patients. TC cells were treated with Vemurafenib and cell apoptosis and viability were analyzed by flow cytometry and MTT assay. Monolayer and sphere cells were isolated from ATC cells to detect the mRNA level of stem cell markers and differentiation markers by RT-PCR. Phosphor-STAT3 level in sphere and monolayer cells was tested by Western blotting. The xenotransplantation animal model has established to analyze the anti-tumor effect of Vemurafenib and Stattic combinational therapy. Undifferentiated TC cells were resistant to Vemurafenib treatment. Sphere cells isolated from ATC showed no significant change in cell viability and apoptosis upon Vemurafenib treatment, and expressed a high level of stem cell marker and phosphor-STAT3. STAT3 inhibition enhanced the tumorigenic capacity and increased Vemurafenib sensitivity in ATC cell lines. Stattic significantly enhanced anti-tumor effect of Vemurafenib in mouse model. Our findings demonstrate that the combinational therapy of Vemurafenib and Stattic is an effective therapeutic treatment for ATC patients.
The bioflavonoid troxerutin prevents gestational hypertension in mice by inhibiting STAT3 signaling
HYPERTENSION RESEARCH
Authors: Li, Yuan; Yang, Xiuzhi; Sun, Qi; Duan, Bide; Wang, Yanyun
Abstract
Gestational hypertension is a high-risk disease for women, and the current treatments have limited efficacies. Here, we aimed to evaluate troxerutin, which is a natural monomer of flavone, in the treatment of gestational hypertension. Pregnant mice with or without pregnancy-induced hypertension (PIH) were treated with troxerutin (20 and 40 mg/kg) or vehicle. Blood pressure and proteinuria were monitored during treatment. The expression of vasodilation converting enzyme (VCE), angiotensin, TNF alpha, IL-6, IL-1 beta and IL-10 was measured by enzyme-linked immunosorbent assay (ELISA). Oxidative stress was assessed by measuring the reactive oxygen species (ROS) levels and antioxidant enzyme concentrations. Western blot analysis was used to assess the expression of p-STAT3, STAT3, SHP-1, and RNF6. Troxerutin reduced blood pressure and the expression of VCE, angiotensin, urinary protein and pro-inflammatory cytokines in a dose-dependent manner while increasing the expression of anti-inflammatory cytokines. The levels of ROS were decreased, and the levels of antioxidant enzymes were increased. Troxerutin treatment significantly suppressed STAT3/RNF6 signaling. Overexpression of RNF6 attenuated the effects of troxerutin in ameliorating inflammation and oxidative stress. Our data support the use of troxerutin for reducing gestational hypertension due to the role of troxerutin in reducing inflammation and oxidative stress.