BACKGROUNDThe research of G protein-coupled receptors (GPCRs) is a promising strategy for drug discovery. In cancer therapy, there is a need to discover novel agents that can inhibit proliferation and induce apoptosis in cancer cells. JTC-801 is a novel GPCR antagonist with the function of reversing pain and anxiety symptoms. This study aims to investigate the antitumor effects of JTC-801 on human osteosarcoma cells (U2OS) and elucidate the underlying mechanism.MATERIALS AND METHODSThe Cell Counting Kit-8 assay was used to detect the viability of U2OS cells treated with JTC-801 in vitro. The cell apoptosis was evaluated using a flow cytometry assay with Annexin V-FITC/PI double staining. The inhibitory effect of JTC-801 on invasion and migration of U2OS cells were determined by the Transwell assays. Western blot assay was performed to measure the levels of proteins related to cell apoptosis and its mechanism.RESULTSThe JTC-801 significantly decreased the viability of U2OS cells (p < .05) as a result of its anti-proliferative effect through induction of apoptosis associated with activation of BAX, Caspase-3 and down-regulating BCL-2 expression. The invasive and migratory cells were obviously reduced after JTC-801 treatment (p < .05). Further, the phosphorylated AKT, mTOR and active p70 S6 protein kinase in the PI3K/AKT signaling pathway were obviously lessened in the JTC-801 treated U2OS group (p < .05).CONCLUSIONSJTC-801 may exert osteosarcoma cell growth inhibition by promoting cell apoptosis, through PI3K/AKT signaling pathway participation.

2015-12-20·Journal of Clinical Oncology1区 · 医学

Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer

1区 · 医学

Article

作者: Kumar, Pankaj ; Takebe, Naoko ; Horiba, Margit N ; Nattam, Sreenivasa R ; Xu, Peng ; Stadler, Walter M ; de Sauvage, Frederic J ; Henderson, Les ; Sleckman, Bethany ; Cohen, Deirdre ; Rajdev, Lakshmi ; Catenacci, Daniel V T ; Marsh, Robert ; Lenz, Heinz-Josef ; Junttila, Melissa R ; Karrison, Theodore ; Kindler, Hedy L ; Kozloff, Mark ; Salgia, Ravi ; Wade, James ; Wang, Xi ; Wallace, James ; Bahary, Nathan ; Stiff, Patrick

Purpose Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models. Patients and Methods Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (KrasG12D; p16/p19fl/fl; Pdx1-Cre and KrasG12D; p53R270H/wt; Pdx1-Cre) were studied. Results No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model. Conclusion The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

1990-02-01·Circulatory shock

Microvascular vasopressin effects during endotoxin shock in the rat.

Article

作者: Baker, C H ; Dietz, J R ; Zhou, Z ; Sutton, E T

We have demonstrated decreased microvascular sensitivity to norepinephrine during endotoxin shock possibly related to reduced sympathetic receptor activity (Baker et al.: Circ Shock 12:165-176, 1984). The response to other vascular controls such as arginine vasopressin (AVP) may also be altered. Reactivity of the left cremaster muscle microvessels of pentobarbital anesthetized Wistar rats was studied using videomicroscopy and videodensitometry. Femoral arterial pressure (Pm), dose response curves of vessel diameters to topical arginine vasopressin (10(-15) to 10(-6) M), FITC-albumin mean transit times, and plasma velocities were obtained. Escherichia coli endotoxin (6 mg/kg i.v., LD100) was infused over a 1-hr period. Parameter measurements were repeated at 30 min and 90 min post-endotoxin. Both Pm and plasma velocities progressively decreased. Arteriolar constriction and the mean transit times of FITC-labeled albumin progressively increased. The threshold dose for AVP averaged 10(-9) M at control and decreased to 10(-14) M post-endotoxin. Venular diameters were not altered by AVP. The AVP antagonist did not alter the microvascular diameter response to endotoxin but did block the responses to topical and endogenous AVP since arterial pressure and flow velocity decreased at a significantly greater rate than in rats without antagonist. Plasma AVP levels were significantly increased by endotoxin. Reduced alpha adrenergic sensitivity may unmask the responsiveness to AVP or increase the sensitivity of AVP receptors. Increased endogenous AVP may require a smaller exogenous concentration of AVP for constriction.

100 项与 GPCR 拮抗剂 (和其瑞医药) 相关的药物交易

登录后查看更多信息