Showing papers on "Growth factor receptor inhibitor published in 2004"
TL;DR: It is shown that H2O2 produced in response to stimulation of cells with epidermal growth factor or platelet-derived growth factor potentiates PIP3 generation and activation of the protein kinase Akt induced by these growth factors, and that peroxiredoxin likely participates in PIP2 signaling by modulating the local concentration of H2 O2.
Abstract: Stimulation of cells with various peptide growth factors induces the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) through activation of phosphatidylinositol 3-kinase. The action of this enzyme is reversed by that of the tumor suppressor PTEN. With the use of cells overexpressing NADPH oxidase 1 or peroxiredoxin II, we have now shown that H2O2 produced in response to stimulation of cells with epidermal growth factor or platelet-derived growth factor potentiates PIP3 generation and activation of the protein kinase Akt induced by these growth factors. We also show that a small fraction of PTEN molecules is transiently inactivated as a result of oxidation of the essential cysteine residue of this phosphatase in various cell types stimulated with epidermal growth factor, platelet-derived growth factor, or insulin. These results suggest that the activation of phosphatidylinositol 3-kinase by growth factors might not be sufficient to induce the accumulation of PIP3 because of the opposing activity of PTEN and that the concomitant local inactivation of PTEN by H2O2 might be needed to increase the concentration of PIP3 sufficiently to trigger downstream signaling events. Furthermore, together with previous observations, our data indicate that peroxiredoxin likely participates in PIP3 signaling by modulating the local concentration of H2O2.
607 citations
TL;DR: Recent work has shown that inhibiting tumor angiogenesis increases the effectiveness of coadministered chemotherapy and radiotherapy, suggesting that drugs that target VEGF or its receptors can be combined with traditional treatment modalities to ensure maximum effectiveness.
Abstract: The development of a vascular supply is a critical factor in the growth and metastatic spread of malignant tumors. Of the multitude of growth factors that regulate physiological and pathological angiogenesis, vascular endothelial growth factor (VEGF) is believed to be the most important. There is evidence that overexpression of VEGF is correlated with an adverse prognosis, at least in some tumors. Tumor-expressed VEGF is particularly attractive as a target for anticancer therapy because its angiogenesis-promoting activity is at the level of the endothelial cell and, compared with agents that directly target tumor cells, tumor penetration is less critical for VEGF inhibitors. Moreover, recent work has shown that inhibiting tumor angiogenesis increases the effectiveness of coadministered chemotherapy and radiotherapy. This suggests that drugs that target VEGF or its receptors can be combined with traditional treatment modalities to ensure maximum effectiveness. A variety of agents aimed at blocking VEGF or its receptor-signaling system are currently being developed for the treatment of cancer. Of these, bevacizumab, a humanized monoclonal antibody directed at VEGF, is the most advanced in clinical development and has shown promising results in clinical trials.
560 citations
TL;DR: It is proposed that beneficial and destructive mediators are either released from separate granules or much smaller vesicles regulated by selectively distinct signals, such as tumor-derived oxidized polyamines or nitric oxide from new endothelial cells.
345 citations
TL;DR: Data indicate that AEE788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters, and is currently in Phase I clinical trials in oncology.
Abstract: Aberrant epidermal growth factor receptor (EGFR) and ErbB2 expression are associated with advanced disease and poor patient prognosis in many tumor types (breast, lung, ovarian, prostate, glioma, gastric, and squamous carcinoma of head and neck). In addition, a constitutively active EGFR type III deletion mutant has been identified in non-small cell lung cancer, glioblastomas, and breast tumors. Hence, members of the EGFR family are viewed as promising therapeutic targets in the fight against cancer. In a similar vein, vascular endothelial growth factor (VEGF) receptor kinases are also promising targets in terms of an antiangiogenic treatment strategy. AEE788, obtained by optimization of the 7H-pyrrolo[2,3-d]pyrimidine lead scaffold, is a potent combined inhibitor of both epidermal growth factor (EGF) and VEGF receptor tyrosine kinase family members on the isolated enzyme level and in cellular systems. At the enzyme level, AEE788 inhibited EGFR and VEGF receptor tyrosine kinases in the nm range (IC(50)s: EGFR 2 nm, ErbB2 6 nm, KDR 77 nm, and Flt-1 59 nm). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC(50)s: 11 and 220 nm, respectively). AEE788 demonstrated antiproliferative activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. Strikingly, AEE788 also inhibited VEGF-induced angiogenesis in a murine implant model. Antiangiogenic activity was also apparent by measurement of tumor vascular permeability and interstitial leakage space using dynamic contrast enhanced magnetic resonance imaging methodology. Taken together, these data indicate that AEE788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. Consequently, AEE788 is currently in Phase I clinical trials in oncology.
343 citations
TL;DR: It is demonstrated that anandamide, Δ9-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells and thereby contribute to cancer progression in patients.
Abstract: Cannabinoids, the active components of marijuana and their endogenous counterparts were reported as useful analgetic agents to accompany primary cancer treatment by preventing nausea, vomiting, and pain and by stimulating appetite. Moreover, they have been shown to inhibit cell growth and to induce apoptosis in tumor cells. Here, we demonstrate that anandamide, Delta(9)-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity. EGFR signal transactivation was identified as the mechanistic link between cannabinoid receptors and the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signaling. Depending on the cellular context, signal cross-communication was mediated by shedding of proAmphiregulin (proAR) and/or proHeparin-binding epidermal growth factor-like growth factor (proHB-EGF) by tumor necrosis factor alpha converting enzyme (TACE/ADAM17). Taken together, our data show that concentrations of THC comparable with those detected in the serum of patients after THC administration accelerate proliferation of cancer cells instead of apoptosis and thereby contribute to cancer progression in patients.
284 citations
TL;DR: Leiomyoma growth is integrally regulated by the complex cross-talk between sex steroid hormones and growth factors, and there is further evidence to suggest that the interactions between estrogen receptors and progesterone receptors may be involved in the modulation of gene transcription activity in leiomyomas.
Abstract: Uterine leiomyomas develop during the reproductive years and regress after menopause, indicating ovarian steroiddependent growth potential. Although the clinical and biochemical observations have traditionally supported an important role for estrogen in the promotion of leiomyoma growth, there is also increasing evidence to suggest the involvement of progesterone in the pathogenesis of leiomyoma. In this review, much attention has been paid to characterizing the molecular mechanisms of sex steroidal regulation of leiomyoma growth and apoptosis by evaluating the effects of sex steroids on the expression of growth factors and apoptosis-related factors. The effects of GnRH agonist on the expression of these factors in leiomyoma are also described. 17b-Estradiol up-regulates epidermal growth factor (EGF) receptor, but down-regulates p53 protein in leiomyoma cells, whereas progesterone augments EGF and Bcl-2 protein, but inhibits insulin-like growth factor (IGF-I) and tumour necrosis factor (TNFa). Since it is now evident that EGF and IGF-I act as local factors which stimulate leiomyoma growth, these findings suggest that progesterone may have dual actions, stimulatory and inhibitory, on leiomyoma cell growth and survival, depending on the local growth factor conditions around each leiomyoma. This may explain why the size of uterine leiomyomas during the use of levonorgestrel-releasing intrauterine system (LNG-IUS) increases in some but decreases in other instances. This may also explain why the size of leiomyomas during pregnancy does not increase despite the overwhelming increase in circulating concentrations of sex steroid hormones. Moreover, there is further evidence to suggest that the interactions between estrogen receptors and progesterone receptors may be involved in the modulation of gene transcription activity in leiomyoma. This review demonstrates that leiomyoma growth is integrally regulated by the complex cross-talk between sex steroid hormones and growth factors.
265 citations
TL;DR: The results suggest that the combination of histone deacetylase inhibitors and VEGF receptor inhibitors may target multiple pathways in tumor progression and angiogenesis and represents a novel therapeutic approach in cancer treatment.
Abstract: Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. Vascular endothelial growth factor (VEGF) and VEGF receptors represent critical molecular targets for antiangiogenesis therapy. In this study, we investigated the biological effect of the histone deacetylase inhibitor NVP-LAQ824 in combination with the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on tumor growth and angiogenesis. We report that treatment with NVP-LAQ824 affected tumor and endothelial cells and was associated with increased histone acetylation, p21 up-regulation, and growth inhibition. In addition, NVP-LAQ824 treatment inhibited the expression of angiogenesis-related genes such as angiopoietin-2, Tie-2, and survivin in endothelial cells and down-regulated hypoxia-inducible factor 1-α and VEGF expression in tumor cells. Combination treatment with NVP-LAQ824 and PTK787/ZK222584 was more effective than single agents in inhibiting in vitro and in vivo VEGF-induced angiogenesis. Endothelial cell proliferation, tube formation, and invasion into the Matrigel plugs were reduced. In mouse models with established subcutaneous prostate (PC3) and orthotopic breast tumors (MDA-MB321), this combination treatment induced 80 to 85% inhibition of tumor growth without overt toxicity. These results suggest that the combination of histone deacetylase inhibitors and VEGF receptor inhibitors may target multiple pathways in tumor progression and angiogenesis and represents a novel therapeutic approach in cancer treatment.
236 citations
TL;DR: An alternative possibility, however, is that IGF-1 initiates a survival pathway aimed at compensating local vascular cell apoptosis (see section III.C.3) to assess the possible benefits of lowering IGF- 1 levels.
Abstract: Recent advances in cardiology have focused on proliferation and regeneration as potential cardiovascular defense mechanisms. Within this framework, growth factors are acquiring increasing importance; insulin-like growth factor-1 (IGF-1) emerges among them for its versatile pleiotropic actions. This review provides a current perspective on IGF-1 and vascular disease.
The IGF-1 system is dynamic and complex,1,2 involving at least 6 IGF-1–binding proteins (IGFBP-1 through -6) and several binding protein–related proteases,1 including pregnancy-associated plasma protein-A (PAPP-A). The latter promotes IGF-1 bioavailability by cleaving IGFBP-4 and -5.3 Acute coronary syndromes have been associated with raised PAPP-A concentrations in blood, leading to the interpretation that PAPP-A may enhance the risk of coronary artery disease through increased IGF-1 in vascular tissues.4 Recent results, however, suggest a different relation between IGF-1 and ischemic syndromes.
Indirect data have supported the concept that IGF-1 may be atherogenetic because it can induce vascular smooth muscle cell (VSMC) proliferation in vitro.5 Early studies on VSMCs from human and rabbit atherosclerotic arteries showed enhanced staining for IGF-1 and its receptor6,7 compared with normal tissues,7 with further enhancement after experimental angioplasty.7 Thus, IGF-1 has been considered a promoter of arterial obstructive lesions8; an alternative possibility, however (consistent with the higher IGF-1 expression after angioplasty), is that IGF-1 initiates a survival pathway aimed at compensating local vascular cell apoptosis (see sections III.C.3 and III.C.4).
Randomized trials of the somatostatin analogue, angiopeptin, have been performed in the setting of postangioplasty restenosis and heart transplant vasculopathy to assess the possible benefits of lowering IGF-1 levels.9 Somatostatin analogues, however, have multiple actions: They reduce growth hormone (GH) release and the serum concentrations of other growth factors (epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor [VEGF]) in addition to IGF-1,10,11 …
236 citations
TL;DR: Growth factors, their function and mechanisms of action as well as the interplay between different growth factors based on recent in vitro and in vivo studies are presented.
210 citations
TL;DR: Transactivation of EGF-R appears to be a major mechanism whereby activation of PAR2 results in colon cancer cell growth, and the role of Src plays a permissive role for PAR2-mediated ERK1/2 activation and cell proliferation, probably acting downstream of the E GF-R.
207 citations
TL;DR: The first time use of a recombinant BsAb for targeting two tumor-associated molecules on either a single or adjacent tumor cells for enhanced antitumor activity is described, underscore the benefits of simultaneous targeting multiple growth factor receptor pathways for more efficacious cancer treatment.
TL;DR: This case of secondary PCL is interesting due to the unusual skin lesions limited to the needle and catheter insertion sites, and no clear explanation for tumour cell implantation and proliferation at the needle tract or portal site.
Abstract: progression and pulmonary haemorrhage. Primary or metastatic haematopoietic neoplasia along a needle tract or portal site has rarely been reported. Fisher et al. reported that mechanical, chemical or surgical trauma will promote the localization of intravenous or intra-arteriolar tumour cells at a trauma site. In our patient, the insertion of needles and the catheter must have produced unavoidable mechanical and surgical trauma, even though they had been removed 28 days prior to the clinical manifestation of the tumour cells. None the less, the possibility of minimal extravasation of blood along the puncture site of the cephalic vein or subclavian vein as a source of haematogenous spread cannot be ruled out. The distribution of the tumours along all the puncture sites suggests that the physical injury produced a favourable environment for metastatic spread during the creation of the needle or catheter tunnel. There is no clear explanation for tumour cell implantation and proliferation at the needle tract or portal site. One possible explanation is that a major disruption of the blood vessel walls with secondary bleeding into the skin and leakage of a sufficient quantity of soluble growth factors and cell mediators into the subcutaneous tissue would lead to a protected environment in which any viable atypical tumour cells could survive and proliferate. Another possible mechanism is associated with trauma-specific and cutaneousspecific tumour cell migration. Preferential expression of specific chemokine receptors on myeloma-derived leukaemic cells may account for migration to specific sites. Release of cytokines, related to trauma, may have played a role in chemokine-mediated recruitment and proliferation of leukaemic cells at these sites. It is possible that tumour cell subclones expressing specific chemokine receptors may have been selected during chemotherapy, resulting in the preferential trafficking of the leukaemic cells to the trauma sites. Swelling along the catheter tracts most commonly indicates a haematoma or an infection. If the index of suspicion for tumour implantation is low, the initial management may consist of an attempted aspiration after carefully preparing the area. The presence of blood in the aspirate suggests a haematoma, whereas an infection will be demonstrated by a positive culture. However, if blood is not obtained and an infection cannot be determined, a biopsy will be needed. In our patient, the tumour mass was somewhat harder on palpation than a normal haematoma, and aspiration and bacterial culture were both negative. Therefore, in a rapidly progressing disease with the presence of subcutaneous nodules elsewhere, as our patient, a biopsy will be necessary for making a differential diagnosis. As leukaemia cutis is considered to be a poor prognostic sign in patients with systemic leukaemia, accurate identification of leukaemia cutis is important for management of the disease. Conventional chemotherapy regimens are advocated in leukaemia cutis. Small skin lesions may be successfully treated by surgical removal or local radiotherapy. Whole body electron-beam radiation therapy is considered to be beneficial in widespread skin involvement. Our patient received combination chemotherapy different from the previous chemotherapeutic regimen, but there was no improvement. In conclusion, this case of secondary PCL is interesting due to the unusual skin lesions limited to the needle and catheter insertion sites. The tumour cell infiltrate appeared to have developed at these sites. Therefore, careful attention should be given to vascular access in such patients.
TL;DR: The preliminary results suggest an increase in response rate and time to progression with the combination of cetuximab and chemotherapy in both disease models and the identification of biologic predictors of response, combination with other targeted agents, and their utilisation in earlier stage malignancies.
Abstract: The epidermal growth factor receptor (EGFR) is a member of the erbB family of tyrosine kinase receptors (RTK). The EGFR is involved in cell proliferation, metastasis and angiogenesis, and is expressed in a large proportion of epithelial tumours. The two main classes of EGFR inhibitors in clinical trials are the RTK inhibitors and the monoclonal antibodies. The clinical development of EGFR inhibitors has introduced new challenges to the design of phase I, II, and III trials. Both classes of agents can be safely administered at doses sufficient to inhibit the EGFR system. Receptor tyrosine kinase inhibitors have been extensively evaluated in non-small-cell lung cancer. In this setting, gefitinib has demonstrated activity in patients who fail initial chemotherapy. Monoclonal antibodies have been developed in combination with cytotoxic chemotherapy in several tumour types, most notably colorectal and head and neck cancer. The preliminary results suggest an increase in response rate and time to progression with the combination of cetuximab and chemotherapy in both disease models. Future issues in the development of EGFR inhibitors include the identification of biologic predictors of response, combination with other targeted agents, and their utilisation in earlier stage malignancies.
TL;DR: It is shown that integrin-induced signalling pathways are necessary for EGF-dependent transcriptional response, demonstrating the requirement of the co-operation between cell-matrix adhesion and EGFR to achieve full biological responses.
Abstract: Integrin signalling co-ordinates with signalling originating from growth factor receptors in the co-operative control of cell proliferation, survival and migration. Increasing evidence suggests that integrins form physical complexes at the cell membrane with growth factor receptors, giving rise to signalling platforms at the adhesive sites. It is probable that at these sites integrins regulate adhesion and at the same time physically constrain and direct the response to soluble growth factors towards proliferation or survival stimuli. These co-operative effects might depend on integrin ability to activate growth factor receptors. In the present paper, we summarize our recent study showing that integrin-dependent adhesion triggers ligand-independent EGFR (epidermal growth factor receptor) activation to transduce downstream signalling. In addition, we also show that integrin-induced signalling pathways are necessary for EGF-dependent transcriptional response, demonstrating the requirement of the co-operation between cell–matrix adhesion and EGFR to achieve full biological responses.
TL;DR: A new class of “matrikine” ligand may be critical for wound healing, as the majority of known extracellular matrix components possessing matrikines play a strong role, or are presented uniquely, during skin repair.
Abstract: Recently, extracellular matrix components have been shown to contain domains that can interact with and activate receptors with intrinsic tyrosine kinase activity. These receptor tyrosine kinases are strong mediators of the cell responses of proliferation, migration, differentiation, and dedifferentiation. However, an interesting question is raised as to why cells would present growth factor receptor ligands in such a manner, as the majority of growth factors are small, soluble, or only transiently tethered ligands. With the exception of the discoidin domain receptors that bind collagen, the other described domains interact with a receptor that binds ubiquitous soluble peptide growth factors, the epidermal growth factor receptor. Unlike traditional growth factors, these individual "matrikine" domains within tenascin-C, laminin, collagen, and decorin possess relatively low binding affinity (high nanomolar or micromolar) and are often presented in multiple valency. The presentation of ligands within the extracellular matrix in this fashion might allow for unique biochemical and physiological outcomes. This new class of "matrikine" ligand may be critical for wound healing, as the majority of known extracellular matrix components possessing matrikines play a strong role, or are presented uniquely, during skin repair. Tenascin-C expression, for instance, is uniquely regulated spatially and has been proposed to present pro-migratory tracks during skin repair through its epidermal growth factor-like repeats. The epidermal growth factor-like repeats of laminin-5 act as cryptic ligands revealed upon matrix metalloproteinase-2 degradation of the surrounding extracellular matrix. The deletion of the discoidin domain receptors 1 and 2 for collagen have negative consequences on the role of fibroblasts and epithelial cells for matrix metalloproteinase production, migration, proliferation, and extracellular matrix turnover. Finally, decorin can bind to, inhibit, and down-regulate epidermal growth factor receptor levels and signaling, suggesting a tonic role of the epidermal growth factor binding domain of decorin in the resolution of wound healing. We provide a model framework for further studies into this emerging class of signals.
TL;DR: The preclinical evidence for activation of the epidermal growth factor receptor (EGFR) in promoting angiogenesis and the efficacy of anti-EGFR agents in inhibiting angiogenic and tumor growth is focused on.
Abstract: This article focuses on the preclinical evidence for activation of the epidermal growth factor receptor (EGFR) in promoting angiogenesis and the efficacy of anti-EGFR agents in inhibiting angiogenesis and tumor growth.
TL;DR: Two related oocyte-derived members of the transforming growth factor-beta (TGF-beta) superfamily, namely growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), have recently been shown to be essential for ovarian follicular growth.
TL;DR: Three major strategies to develop new ErbB-targeted therapies are reviewed, including monoclonal anti-receptor antibodies, specific tyrosine kinase inhibitors and antagonists of heat shock protein 90.
TL;DR: The mitogenic effects of leptin on cancer cells, in combination with the increased migration and expression of growth factors, overall likely contributes to the progression of prostate cancer.
Abstract: Background The adipocyte hormone leptin has been shown to increase migration and angiogenesis in epithelial cells. Therefore, we hypothesized that leptin would induce prostate cancer cell migration and growth factor expression in vitro. Methods Prostate cancer cell lines DU145 and PC-3 (androgen-resistant) were treated with leptin over time. Supernatants were assayed for growth factor expression via enzyme-linked immunosorbent assay (ELISA). Becton Dickinson-Falcon Transwell systems were used to assay leptin-induced migration. Results Leptin significantly induced expression of vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and basic fibroblast growth factor (bFGF) in DU145 and PC-3 cells. Prostate cancer cell migration was enhanced by leptin and inhibited 50% to 70% with the addition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) inhibitors. Conclusions The mitogenic effects of leptin on cancer cells, in combination with the increased migration and expression of growth factors, overall likely contributes to the progression of prostate cancer. Therefore, obesity associated with high leptin levels should be considered a risk factor in prostate cancer patients.
TL;DR: An ideal marker of implantation is sensitive and specific, and easy to obtain without disturbing implantation, and Glycodelin and leukaemia inhibitory factor (serum) and integrins and pinopodes (biopsies) are promising candidates.
Abstract: A pregnancy rate of approximately 15% per cycle renders the process of human reproduction inefficient. The cycle-dependent expression of molecules involved in the embryo-endometrial dialogue has lead to the identification of a 'window of implantation'. This is the unique temporal and spatial expression of factors that allows the embryo to implant (via signalling, appositioning, attachment and invasion) in a specific time frame of 48 h, 7-10 days after ovulation. Integrin molecules, L-selectin ligands, mucin-1, heparin-binding epidermal growth factor and pinopodes are involved in appositioning and attachment. The embryo produces cytokines and growth factors [interleukins, prostaglandins, vascular endothelial growth factor (VEGF)] and receptors for endometrial signals (leukaemia inhibitory factor receptor, colony stimulating factor receptor, insulin-like growth factors and heparin binding epidermal growth factor receptor). The immune system plays an important role. Immunomodulatory factors such as glycodelin, inhibin and interleukin prevent a graft-versus-host reaction. Angiogenesis controlled by VEGF and prostaglandins is needed for formation of a receptive endometrium and a placenta. Identification of these factors has led to their use as markers of implantation that may identify defects causing subfertility. An ideal marker of implantation is sensitive and specific, and easy to obtain without disturbing implantation. Glycodelin and leukaemia inhibitory factor (serum) and integrins and pinopodes (biopsies) are promising candidates.
TL;DR: This work identifies a mechanism via which VEGF(165) interacting with its receptor VEGFR-2 rapidly induces prourokinase activation that is dependent on a change in integrin affinity, activation of matrix metalloproteinase 2 (MMP-2), and pro-uPA being bound to its surface receptor uPAR.
Patent•
06 Dec 2004TL;DR: In this paper, the authors proposed a novel vascular endothelial growth factor receptor (VEGFR)-binding polypeptides and methods for using them to inhibit biological activities mediated by VEGFs.
Abstract: The present disclosure relates to novel vascular endothelial growth factor receptor (VEGFR)-binding polypeptides and methods for using these polypeptides to inhibit biological activities mediated by vascular endothelial growth factors (VEGFs). The present disclosure also provides various improvements relating to single domain binding polypeptides.
TL;DR: Silibinin/ silymarin inhibits the growth of in vivo advanced human prostate tumor xenograft in nude mice and synergizes the therapeutic effects of doxorubicin in PCA cells, making it a strong candidate for combination chemotherapy.
Abstract: Several epigenetic alterations leading to constitutively active mitogenic and cell-survival signaling, and loss of apoptotic response are causally involved in self-sufficiency of prostate cancer (PCA) cells toward uncontrolled growth, and increased secretion of pro-angiogenic factors. Therefore, one targeted approach for PCA prevention, growth control and/or treatment could be inhibition of epigenetic molecular events involved in PCA growth, progression and angiogenesis. In this regard, silibinin/silymarin (silibinin is the major active compound in silymarin) has shown promising efficacy. Our extensive studies with silibinin/silymarin and PCA cells have shown the pleiotropic anticancer effects leading to cell growth inhibition in culture and nude mice. The underlying mechanisms of silibinin/silymarin efficacy against PCA involve alteration in cell cycle progression, and inhibition of mitogenic and cell survival signaling, such as epidermal growth factor receptor, insulin-like growth factor receptor type I and nuclear factor kappa B signaling. Silibinin also synergizes the therapeutic effects of doxorubicin in PCA cells, making it a strong candidate for combination chemotherapy. Silibinin/ silymarin also inhibits the secretion of proangiogenic factors from tumor cells, and causes growth inhibition and apoptotic death of endothelial cells accompanied by disruption of capillary tube formation on Matrigel. More importantly, silibinin inhibits the growth of in vivo advanced human prostate tumor xenograft in nude mice. Recently, due to its non-toxic and mechanism-based strong preventive/therapeutic efficacy, silibinin has entered in phase I clinical trial in prostate cancer patients.
TL;DR: Several PF4 fragments such as PF4-CTF and modified molecules have been made that exhibit antiangiogenesis properties and may serve as leads for further therapeutic development.
Abstract: Platelet factor 4 (PF4) is an antiangiogenic ELR-negative chemokine. PF4 inhibits endothelial cell proliferation and migration and angiogenesis in vitro and in vivo. Three different mechanisms have been proposed to explain PF4's antiangiogenic effects. First, PF4 may bind proteoglycans and interfere with the proteoglycan-bystander effect on growth factor activity. Second, PF4 is able to interact directly with angiogenesis growth factors such as fibroblast growth factors or vascular endothelial growth factors and inhibits their interaction with cell surface receptors. Third, PF4 may activate cell surface receptors on endothelial cells and induce inhibitory signals. Recently, one such receptor, CXCR3-B, was identified. In cardiovascular disease, PF4 may possibly intervene in collateral vessel formation, plaque neovascularization, heparin-induced thrombocytopenia and stent endothelialization. Several PF4 fragments such as PF4-CTF and modified molecules have been made that exhibit antiangiogenesis properties and may serve as leads for further therapeutic development.
TL;DR: This article focuses on illustrating the relationship between growth factor signaling and antiestrogen failure in the authors' in-house tumor models of breast cancer and describing how it is now beginning to successfully target growth factor activity to improve the effects of antiestrogens drugs and to block aggressive disease progression.
Abstract: An increasing body of evidence demonstrates that growth factor networks are highly interactive with estrogen receptor signaling in the control of breast cancer growth. As such, tumor responses to antiestrogens are likely to be a composite of the estrogen receptor and growth factor-inhibitory activity of these agents, with alterations/aberrations in growth factor signaling providing a mechanism for the development of antiestrogen resistance. In this light, the current article focuses on illustrating the relationship between growth factor signaling and antiestrogen failure in our in-house tumor models of breast cancer and describing how we are now beginning to successfully target growth factor activity to improve the effects of antiestrogen drugs and to block aggressive disease progression.
TL;DR: A novel role for the mitochondrion is established as a proximal target specific to H2O2-induced signaling and growth factor transactivation in growth factor receptors and mitochondrial function.
TL;DR: In the present investigation, ART was found also to inhibit angiogenesis in vivo and in vitro, indicating that ART was selectively against HUVEC.
Abstract: Artesunate (ART) is a semi-synthetic derivative of artemisinin extracted from the plant Artemisia annua is a safe and effective antimalarial drug. In the present investigation, ART was found also to inhibit angiogenesis in vivo and in vitro. The anti-angiogenic effect in vivo was evaluated in nude mice by means of human ovarian cancer HO-8910 implantation and immunohistochemical stainings for microvessel (CD 31 ), vascular endothelial growth factor (VEGF) and VEGF receptor KDR/flk-1. Tumor growth was decreased and microvessel density was reduced following drug treatment with no apparent toxicity to the animals. ART also remarkably lowered VEGF expression on tumor cells and KDR/flk-1 expression on endothelial cells as well as tumor cells. The in vitro effect of ART was tested on models of angiogenesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). The results showed that ART significantly inhibited angiogenesis in a dose-dependent form in the range of 0.5∼50 µmol/l. Additionally, the inhibitory effect of ART on HVUEC proliferation was stronger than that on Hela, JAR, HO-8910 cancer cells, NIH-3T3 fibroblast cells and human endometrial cells, indicating that ART was selectively against HUVEC. These findings and the known low toxicity of ART are clues that ART may be a promising angiogenesis inhibitor.
TL;DR: It is reported that activating mutations in FGFR3 increase the stability of the receptor and the lysosomal targeting defect is additive to other mechanisms proposed to explain the pathogenesis of ACH.
Abstract: Mutations of fibroblast growth factor receptor 3 (FGFR3) are responsible for achondroplasia (ACH) and related dwarfing conditions in humans. The pathogenesis involves constitutive activation of FGFR3, which inhibits proliferation and differentiation of growth plate chondrocytes. Here we report that activating mutations in FGFR3 increase the stability of the receptor. Our results suggest that the mutations disrupt c-Cbl-mediated ubiquitination that serves as a targeting signal for lysosomal degradation and termination of receptor signaling. The defect allows diversion of actively signaling receptors from lysosomes to a recycling pathway where their survival is prolonged, and, as a result, their signaling capacity is increased. The lysosomal targeting defect is additive to other mechanisms proposed to explain the pathogenesis of ACH.
TL;DR: ErbBB2 is identified as a critical component of EGF signaling to the Gab1/Gab2-PI3K-Akt pathway and anchorage-independent growth, but EGF stimulation of MAPK and monolayer growth can occur efficiently without the contribution of ErbB2.
Abstract: Due to heterodimerization and a variety of stimulating ligands, the ErbB receptor system is both diverse and flexible, which proves particularly advantageous to the aberrant signaling of cancer cells. However, specific mechanisms of how a particular receptor contributes to generating the flexibility that leads to aberrant growth regulation have not been well described. We compared the utilization of ErbB2 in response to epidermal growth factor (EGF) and heregulin stimulation in colon carcinoma cells. Anti-ErbB2 monoclonal antibody 2C4 blocked heregulin-stimulated phosphorylation of ErbB2 and ErbB3; activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3′-kinase (PI3K), and Akt; proliferation; and anchorage-independent growth. 2C4 blocked EGF-mediated phosphorylation of ErbB2 and inhibited PI3K/Akt and anchorage-independent growth but did not affect ErbB1 or MAPK. Immunoprecipitations showed that ErbB3 and Grb2-associated binder (Gab) 1 were phosphorylated and associated with PI3K activity after heregulin treatment and that Gab1 and Gab2, but not ErbB3, were phosphorylated and associated with PI3K activity after EGF treatment. These data show that monoclonal antibody 2C4 inhibited all aspects of heregulin signaling as well as anchorage-independent and monolayer growth. Furthermore, we identify ErbB2 as a critical component of EGF signaling to the Gab1/Gab2-PI3K-Akt pathway and anchorage-independent growth, but EGF stimulation of MAPK and monolayer growth can occur efficiently without the contribution of ErbB2.
TL;DR: The findings support a novel tumor suppressor function of BRCA1 that is relevant to breast cancer and identify a potential interactive risk factor for women with B RCA1 mutations.
Abstract: BRCA1 mutations and estrogen use are risk factors for the development of breast cancer. Recent work has identified estrogen receptors localized at the plasma membrane that signal to cell biology. We examined the impact of BRCA1 on membrane estrogen and growth factor receptor signaling to breast cancer cell proliferation. MCF-7 and ZR-75-1 cells showed a rapid and sustained activation of extracellular signal-related kinase (ERK) in response to estradiol (E2) that was substantially prevented by wild-type (wt) but not mutant BRCA1. The proliferation of MCF-7 cells induced by E2 was significantly inhibited by PD98059, a specific ERK inhibitor, or by dominant negative ERK2 expression and by expression of wt BRCA1 (but not mutant BRCA1). E2 induced the synthesis of cyclins D1 and B1, the activity of cyclin-dependent kinases Cdk4 and CDK1, and G(1)/S and G(2)/M cell cycle progression. The intact tumor suppressor inhibited all of these. wt BRCA1 also inhibited epidermal growth factor and insulin-like growth factor I-induced ERK and cell proliferation. The inhibition of ERK and cell proliferation by BRCA1 was prevented by phosphatase inhibitors and by interfering RNA knockdown of the ERK phosphatase, mitogen-activated kinase phosphatase 1. Our findings support a novel tumor suppressor function of BRCA1 that is relevant to breast cancer and identify a potential interactive risk factor for women with BRCA1 mutations.