Abstract:Claudin‐4 (CLDN‐4), a tight‐junction protein, is overexpressed in various malignant tumors, including gastric, colorectal, pancreatic, and breast cancers. However, CLDN‐4 is also expressed in normal tissues, including the liver, pancreas, kidney, and small intestine. Whether CLDN‐4 is an effective and safe target for cancer therapy has been unclear owing to the lack of a binder with both CLDN‐4 specificity and cross‐reactivity to human and murine cells. In this study, we successfully generated a rat anti‐CLDN‐… Show more
“…The findings suggest that 4D3 might not evoke pancreatitis. In the study of antibody biodistribution using mouse CLDN4 antibody (5D12), the antibody distribution in pancreatic tissue is not different from the control antibody . The findings suggest that anti‐CLDN4 antibody might not evoke pancreatitis.…”
Claudin (CLDN) family comprises of protein that form a tight junction, and is involved in regulating polarity and differentiation of cells. Here, we aimed to investigate the effects of inhibiting CLDN4 in pancreatic ductal carcinomas (PDC). We first examined 91 cases of human PDC by immunohistochemistry and found that CLDN4 expression was correlated with tumor invasion, nodal metastasis, and distant metastasis. Anti‐CLDN4 extracellular domain antibody, previously established by us (4D3), inhibited the proliferation of MIA‐PaCa‐2 PDC cells and increased intracellular 5‐fluorouracil (5‐FU) concentration with lowering transepithelial electrical resistance. Concurrent treatment of 5‐FU and 4D3 resulted in synergistic inhibition of growth of MIA‐PaCa‐2 cells in nude mice. In addition, MIA‐PaCa‐2 cell tumors treated with full‐dose folfirinox (FFX) decreased tumor diameters to 50%; however, 60% of mice were dead from adverse effects. In contrast, half‐dose FFX concomitant with 4D3 treatment decreased tumors equivalent to full‐dose FFX, but without the adverse effects. These findings suggest that targeting CLDN4 might increase the effectiveness and safety of anticancer drug therapy in PDC.
“…The findings suggest that 4D3 might not evoke pancreatitis. In the study of antibody biodistribution using mouse CLDN4 antibody (5D12), the antibody distribution in pancreatic tissue is not different from the control antibody . The findings suggest that anti‐CLDN4 antibody might not evoke pancreatitis.…”
Claudin (CLDN) family comprises of protein that form a tight junction, and is involved in regulating polarity and differentiation of cells. Here, we aimed to investigate the effects of inhibiting CLDN4 in pancreatic ductal carcinomas (PDC). We first examined 91 cases of human PDC by immunohistochemistry and found that CLDN4 expression was correlated with tumor invasion, nodal metastasis, and distant metastasis. Anti‐CLDN4 extracellular domain antibody, previously established by us (4D3), inhibited the proliferation of MIA‐PaCa‐2 PDC cells and increased intracellular 5‐fluorouracil (5‐FU) concentration with lowering transepithelial electrical resistance. Concurrent treatment of 5‐FU and 4D3 resulted in synergistic inhibition of growth of MIA‐PaCa‐2 cells in nude mice. In addition, MIA‐PaCa‐2 cell tumors treated with full‐dose folfirinox (FFX) decreased tumor diameters to 50%; however, 60% of mice were dead from adverse effects. In contrast, half‐dose FFX concomitant with 4D3 treatment decreased tumors equivalent to full‐dose FFX, but without the adverse effects. These findings suggest that targeting CLDN4 might increase the effectiveness and safety of anticancer drug therapy in PDC.
“…Aberrant Claudin 4 expression plays an important role in the clinicopathological characteristics of gastric cancer [58]. Claudin 4 is thus a potent target for cancer therapy, and that an anti-Claudin 4 antibody is a promising candidate anticancer agent [59, 60]. Fig.…”
BackgroundOridonin, the major terpene found in Rabdosia rubescens (Henmsl.) Hara, is widely used as a dietary supplement and therapeutic drug. Oridonin has been proven to possess good anti-tumour activity, but little is known about its effect on angiogenesis. The aim of this study was to investigate the antiangiogenic effects of oridonin in vivo and in vitro and prove that oridonin anti-tumour activity is based on suppressing angiogenesis.MethodsIn vitro, the antiangiogenesis effect was studied by proliferation, apoptosis, migration, invasion, and tube formation experiments on human umbilical vascular endothelial cells (HUVECs). In vivo, using the Tg (fli1: GFP) zebrafish model, the embryonic vasculogenesis and postnatal regeneration were evaluated. The vascular endothelial growth factor (VEGF) signalling pathway gene expressions were assessed by reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, the inhibition effects on tumour growth and metastasis were observed using a xenograft zebrafish tumour model and xenograft nude mouse tumour model. Angiogenesis was assayed by immunostaining with cluster of differentiation 31. Importantly, the proteins were identified as being differentially expressed in an in vivo model by two-dimensional electrophoresis-mass spectrometry (2D–MS) and western blot (WB).ResultsThe results indicated that oridonin inhibited HUVEC proliferation, migration, invasion, and tube formation and induced cell apoptosis. Oridonin inhibited zebrafish angiogenesis during embryonic development and tail fin regeneration. RT-PCR showed that oridonin decreased the VEGFA, VEGFR2, and VEGFR3 expressions in zebrafish, while the TP53 expression increased. Moreover, oridonin had strong effects on tumour growth and metastasis in vivo. 2D–MS identified a total of 50 proteins differentially expressed (17 up-expressed, 28 down-expressed). Lastly, WB showed that Claudin 1, Claudin 4, and Claudin 7 were closely related to tumour growth and metastasis.ConclusionThis study demonstrated that oridonin could inhibit tumour growth and metastasis, which mainly based on oridonin antiangiogenic effects. Claudin 1, Claudin 4, and Claudin 7 were the main contributors to the mechanism.
“…L cells stably expressing mouse CLDN-5 were provided by Dr. S. Tsukita (Kyoto University, Kyoto, Japan). HT-1080 cells stably expressing human CLDN-1, CLDN-2, CLDN-3, CLDN-4, CLDN-5, CLDN-6, or CLDN-7 were developed as described previously (Hashimoto et al, 2016). P3U1 mouse myeloma cells, MDCKII cells, Phoenix-A packaging cells, and Caco-2 and T84 human intestinal cells were purchased from American Type Culture Collection (Manassas, VA).…”
A current bottleneck in the development of central nervous system (CNS) drugs is the lack of drug delivery systems targeting the CNS. The intercellular space between endothelial cells of the blood-brain barrier (BBB) is sealed by complex protein-based structures called tight junctions (TJs). Claudin-5 (CLDN-5), a tetra-transmembrane protein is a key component of the TJ seal that prevents the paracellular diffusion of drugs into the CNS. In the present study, to investigate whether CLDN-5 binders can be used for delivery of drugs to the CNS, we generated monoclonal antibodies (mAbs) specific to the extracellular domains of CLDN-5. In an in vitro model of the BBB, the anti-CLDN-5 mAbs attenuated trans-epithelial/endothelial electrical resistance and enhanced solute permeation. These anti-CLDN-5 mAbs are potential leads for the development of novel drug delivery systems targeting the CNS.
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