Showing papers on "Growth factor receptor inhibitor published in 2014"

miR-7 inhibits the invasion and metastasis of gastric cancer cells by suppressing epidermal growth factor receptor expression.

Abstract: The present study profiled differentially expressed microRNAs (miRs) in gastric cancer cell lines and then investigated miR-7 expression in gastric cancer tissue specimens and the effects of miR-7 on the growth, invasion and metastasis of gastric cancer cells and the underlying molecular events. A microRNA microarray was used to profile differentially expressed miRNAs in human gastric cancer cell lines relative to a normal stomach mucosal epithelial cell line. The miRNA miR-7 was selected for further investigation, which included real-time reverse-transcription PCR (qRT-PCR) analysis of miR-7 levels in different gastric cancer cell lines and tissues and distant non-tumor tissues from patient resections. Cell counting kit-8 (CCK-8), Transwell migration and invasion, and western blot assays were performed to assess tumor cell viability, invasion and gene expression, respectively, after miR-7 transfection. The miRNA microarray profiling revealed 14 upregulated miRNAs (including miR-21, miR-26b and miR-30b) and 19 downregulated miRNAs (including let-7i, miR-7 and miR-622) between gastric cancer and normal cell lines. The qRT-PCR analysis confirmed that reduced miR-7 expression occurred more frequently in poorly and moderately differentiated gastric cancer MGC-803, MKN-45 and SGC-7901 cell lines than in the well-differentiated gastric cancer NCI-N87 cell line, which was consistent with the results for gastric cancer tissues. Expression of miR-7 was downregulated in 86.9% (20/23) of the gastric cancer tissues compared with that in the distant non-tumor tissues. Restoration of miR-7 expression significantly inhibited tumor cell viability, invasiveness and migration when compared with the control cells. Luciferase assay confirmed the epidermal growth factor receptor (EGFR) as a target gene of mR-7, and expression of miR-7 significantly suppressed EGFR expression at both the mRNA and protein levels. The data from the present study demonstrated that reduced miR-7 expression contributes to gastric cancer development and progression. Further study will investigate miR-7 in the regulation of EGFR expression in vitro and in vivo.

Identification of PLXDC1 and PLXDC2 as the transmembrane receptors for the multifunctional factor PEDF.

Abstract: Pigment Epithelium Derived Factor (PEDF) is a secreted factor that has broad biological activities. It was first identified as a neurotrophic factor and later as the most potent natural antiangiogenic factor, a stem cell niche factor, and an inhibitor of cancer cell growth. Numerous animal models demonstrated its therapeutic value in treating blinding diseases and diverse cancer types. A long-standing challenge is to reveal how PEDF acts on its target cells and the identities of the cell-surface receptors responsible for its activities. Here we report the identification of transmembrane proteins PLXDC1 and PLXDC2 as cell-surface receptors for PEDF. Using distinct cellular models, we demonstrate their cell type-specific receptor activities through loss of function and gain of function studies. Our experiments suggest that PEDF receptors form homooligomers under basal conditions, and PEDF dissociates the homooligomer to activate the receptors. Mutations in the intracellular domain can have profound effects on receptor activities.

Modulation of angiogenesis by thyroid hormone and hormone analogues: implications for cancer management

Abstract: Acting via a cell surface receptor on integrin αvβ3, thyroid hormone is pro-angiogenic. Nongenomic mechanisms of actions of the hormone and hormone analogues at αvβ3 include modulation of activities of multiple vascular growth factor receptors and their ligands (vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, epidermal growth factor), as well as of angiogenic chemokines (CX3 family). Thyroid hormone also may increase activity of small molecules that support neovascularization (bradykinin, angiotensin II) and stimulate endothelial cell motility. Therapeutic angio-inhibition in the setting of cancer may be opposed by endogenous thyroid hormone, particularly when a single vascular growth factor is the treatment target. This may be a particular issue in management of aggressive or recurrent tumors. It is desirable to have access to chemotherapies that affect multiple steps in angiogenesis and to examine as alternatives in aggressive cancers the induction of subclinical hypothyroidism or use of antagonists of the αvβ3 thyroid hormone receptor that are under development.

Epidermal growth factor receptor inhibitors: coming of age.

Abstract: Background:Agents targeting the epidermal growth factor (EGFR)-mediated signaling pathway are used in the treatment of various solid tumors, including lung, breast, pancreatic, colorectal, and head...

Cell and molecular biology of epidermal growth factor receptor.

Abstract: The epidermal growth factor receptor (EGFR) has been one of the most intensely studied cell surface receptors due to its well-established roles in developmental biology, tissue homeostasis, and cancer biology. The EGFR has been critical for creating paradigms for numerous aspects of cell biology, such as ligand binding, signal transduction, and membrane trafficking. Despite this history of discovery, there is a continual stream of evidence that only the surface has been scratched. New ways of receptor regulation continue to be identified, each of which is a potential molecular target for manipulating EGFR signaling and the resultant changes in cell and tissue biology. This chapter is an update on EGFR-mediated signaling, and describes some recent developments in the regulation of receptor biology.

Targeting receptor tyrosine kinases in gastric cancer.

Abstract: Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kinases (RTKs), has been associated with gastric cancer development. Trastuzumab, an inhibitor of ERBB2, has been approved for the treatment of gastric cancer, although other receptor tyrosine kinases, such as epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, c-Met, IGF-1R and fibroblast growth factor receptor 2, are also activated in gastric cancer. The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients. On the other hand, the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients; however, a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial. Other clinical trials, especially phase III trials that have tested drugs targeting RTKs, such as cetuximab, panitumumab, gefitinib, erlotinib, figitumumab, sorafenib, sunitinib and lapatinib, have shown that these drugs have modest effects against gastric cancer. This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.

Targeting insulin-like growth factor-I and insulin-like growth factor-binding protein-3 signaling pathways: A novel therapeutic approach for asthma

Abstract: Insulin-like growth factor (IGF)-I has been recognized to play critical roles in the pathogenesis of asthma, whereas IGF-binding protein (IGFBP)-3 blocks crucial physiologic manifestations of asthma. IGF-I enhances subepithelial fibrosis, airway inflammation, airway hyperresponsiveness, and airway smooth muscle hyperplasia by interacting with various inflammatory mediators and complex signaling pathways, such as intercellular adhesion molecule-1, and the hypoxia-inducible factor/vascular endothelial growth factor axis. On the other hand, IGFBP-3 decreases airway inflammation and airway hyperresponsiveness through IGFBP-3 receptor-mediated activation of caspases, which subsequently inhibits NF-κB signaling pathway. It also inhibits the IGF-I/hypoxia-inducible factor/vascular endothelial growth factor axis via IGF-I-dependent and/or IGF-I-independent mechanisms. This Translational Review summarizes the role of IGF-I and IGFBP-3 in the context of allergic airway disease, and discusses the therapeutic potential of various strategies targeting the IGF-I and IGFBP-3 signaling pathways for the management of asthma.

Role of epidermal growth factor receptor in vascular structure and function.

Abstract: Purpose of the reviewThe epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase with a wide implication in tumor biology, wound healing and development. Besides acting as a growth factor receptor activated by ligands such as EGF, the EGFR can also be transactivated and thereby mediate

TGF-β Mediated Crosstalk Between Malignant Hepatocyte and Tumor Microenvironment in Hepatocellular Carcinoma.

Abstract: In this article, we have reviewed current literature regarding the regulation of hepatocellular carcinoma (HCC) by the interaction of malignant hepatocytes and their tissue environment through cytokine signaling, here represented by transforming growth factor-beta (TGF-β) signaling. We have discussed responses of TGF-β signaling in transition of hepatic stellate cells to myofibroblasts (MFBs), recruitment of tumor-associated macrophages (TAMs), and enrichment of tumor-associated endothelial cells (TECs). The malignant hepatocytes also secrete various factors such as platelet-derived growth factors (PDGFs), vascular endothelial growth factor (VEGF), and TGF-β. TGF-β, a super-family of cytokines, creates tumor microenvironment by interacting through other growth factors (epidermal growth factor receptor (EGFR), PDGF, fibroblast growth factor (FGF), hepatocyte growth factor (HGF), VEGF), cytokines and chemokines, and extracellular matrix (ECM) remodeling. Hence, the HCC tumor microenvironment may now be recognized as an important participant of tumor progression to act as potential target to systemic therapies compared to targeted therapies.

The LRIG family: enigmatic regulators of growth factor receptor signaling

Abstract: The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins contains three vertebrate members (LRIG1, LRIG2 and LRIG3) and one member each in flies (Lambik) and worms (Sma-10). LRIGs have stepped into the spotlight as essential regulators of growth factor receptors, including receptor tyrosine and serine/threonine kinases. LRIGs have been found to both negatively (LRIG1 and LRIG3) and positively (Sma-10 and LRIG3) regulate growth factor receptor expression and signaling, although the precise molecular mechanisms by which LRIGs function are not yet understood. The most is known about LRIG1, which was recently demonstrated to be a tumor suppressor. Indeed, in vivo experiments reinforce the essential link between LRIG1 and repression of its targets for tissue homeostasis. LRIG1 has also been identified as a stem cell marker and regulator of stem cell quiescence in a variety of tissues, discussed within. Comparably, less is known about LRIG2 and LRIG3, although studies to date suggest that their functions are largely distinct from that of LRIG1 and that they likely do not serve as growth/tumor suppressors. Finally, the translational applications of expressing soluble forms of LRIG1 in LRIG1-deficient tumors are being explored and hold tremendous promise.

Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages

Abstract: Hepatocyte growth factor, produced by stromal and follicular dendritic cells, and present at high concentrations in the sera of patients with chronic lymphocytic leukemia, prolongs the survival of leukemic B cells by interacting with their receptor, c-MET. It is, however, unknown whether hepatocyte growth factor influences microenvironmental cells, such as nurse-like cells, which deliver survival signals to the leukemic clone. We evaluated the expression of c-MET on nurse-like cells and monocytes from patients with chronic lymphocytic leukemia and searched for phenotypic/functional features supposed to be influenced by the hepatocyte growth factor/c-MET interaction. c-MET is expressed at high levels on nurse-like cells and at significantly higher levels than normal on monocytes from patients. Moreover, the hepatocyte growth factor/c-MET interaction activates STAT3TYR705 phosphorylation in nurse-like cells. Indoleamine 2,3-dioxygenase, an enzyme modulating T-cell proliferation and induced on normal monocytes after hepatocyte growth factor treatment, was detected together with interleukin-10 on nurse-like cells, and on freshly-prepared patients’ monocytes. Immunohistochemical/immunostaining analyses demonstrated the presence of c-MET+ and indoleamine 2,3-dioxygenase+ cells in lymph node biopsies, co-expressed with CD68 and vimentin. Furthermore nurse-like cells and chronic lymphocytic monocytes significantly inhibited T-cell proliferation, prevented by anti-transforming growth factor beta and interleukin-10 antibodies and indoleamine 2,3-dioxygenase inhibitors, and supported CD4+CD25high+/FOXP3+ T regulatory cell expansion. We suggest that nurse-like cells display features of immunosuppressive type 2 macrophages: higher hepatocyte growth factor levels, produced by leukemic or other microenvironmental surrounding cells, may cooperate to induce M2 polarization. Hepatocyte growth factor may thus have a dual pathophysiological role: directly through enhancement of survival of the leukemic clone and indirectly by favoring T-cell immunosuppression.

The role of endogenous epidermal growth factor receptor ligands in mediating corneal epithelial homeostasis.

Abstract: Purpose To provide a comprehensive study of the biological role and therapeutic potential of six endogenous epidermal growth factor receptor (EGFR) ligands in corneal epithelial homeostasis. Methods Kinetic analysis and dose response curves were performed by using in vitro and in vivo wound-healing assays. Biochemical assays were used to determine receptor expression and activity. Human tears were collected and quantitatively analyzed by multianalyte profiling for endogenous EGFR ligands. Results Epidermal growth factor receptor ligands improved wound closure and activated EGFR, but betacellulin (BTC) was the most efficacious promoter of wound healing in vitro. In contrast, only epidermal growth factor (EGF) promoted wound healing in vivo. Human tears from 25 healthy individuals showed EGFR ligands at these average concentrations: EGF at 2053 ± 312.4 pg/mL, BTC at 207 ± 39.4 pg/mL, heparin-binding EGF at 44 ± 5.8 pg/mL, amphiregulin at 509 ± 28.8 pg/mL, transforming growth factor-α at 84 ± 19 pg/mL, and epiregulin at 52 ± 15 pg/mL. Conclusions Under unwounded conditions, only EGF was present at concentrations near the ligand's Kd for the receptor, indicating it is the primary mediator of corneal epithelial homeostasis. Other ligands were present but at concentrations 11- to 7500-fold less their Kd, preventing significant ligand binding. Further, the high levels of EGF and its predicted binding preclude receptor occupancy by exogenous ligand and can explain the discrepancy between the in vitro and in vivo data. Therefore, therapeutic use of EGFR ligands may be unpredictable and impractical.

Crosstalk between IGF-1R and other tumor promoting pathways

Abstract: Insulin-like growth factor 1 receptor (IGF-1R) is important in cancer pathogenesis and progression. While its signaling pathway is an interesting therapeutic target, recent clinical trials have exhibited limited effects; however, significant crosstalks between IGF- 1R and other signaling pathways have garnered increasing attention. These complex networks include interactions between IGF-1R and receptor tyrosine kinases (RTKs), including insulin receptor (IR), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), mesenchymal-epithelial transition factor (MET), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Furthermore, IGF-1R also is related to steroid hormones, including estrogen receptors alpha and beta (ER! and ER"), androgen receptor (AR), and progesterone receptor (PR). Cumulatively, actions of crosstalk between IGF-1R, and RTKs/steroid hormones promote tumorigenesis, as demonstrated by the effectiveness of recently proposed therapeutic strategies. These therapeutic strategies, primarily pertaining to crosstalk-cotargeting, exhibited notable advantages in overcoming resistance to conventional chemotherapy and conventional endocrine therapy. Furthermore, these techniques offer benefits beyond the limited effects of single- agent targeting previously reported. Thus, the role of crosstalk between IGF-1R and RTKs/steroid hormones, including strategies to block these pathways in combination with recent development in this field, were reviewed and the potential future cancer therapeutics suggested by this rationale were considered.

Restoration of miR-7 expression suppresses the growth of Lewis lung cancer cells by modulating epidermal growth factor receptor signaling.

Abstract: microRNAs are an abundant class of short endogenous non-coding RNAs that function as important regulators of multiple target genes and participate in diverse biological roles in carcinogenesis. However, the role of miR-7 in lung cancer remains unclear and requires further elucidation. In the present study, we found a reduction of miR-7 expression in Lewis lung cancer (3LL) cells originating from mice by real-time RT-PCR. Restoration of miR-7 inhibited 3LL cell proliferation, induced cell apoptosis in vitro and reduced tumorigenicity in vivo. We further confirmed that miR-7 downregulated the expression of both epidermal growth factor receptor (EGFR) and murine leukemia viral oncogene homologue-1 (RAF-1) oncogenes by real-time PCR and western blot analysis. Furthermore, inhibition of EGFR showed similar effects to miR-7 enforcement in 3LL cells. Taken together, these findings revealed that miR-7 acts as an antitumor miRNA in 3LL by targeting and suppressing the expression of both EGFR and RAF-1 oncogenes. This study may provide a rationale for the use of miR-7 in lung cancer target therapy.

Management of acquired resistance to epidermal growth factor receptor kinase inhibitors in patients with advanced non-small cell lung cancer.

Abstract: The widespread adoption of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the first-line treatment of patients with advanced EGFR-mutated non-small cell lung cancer has resulted in acquired tyrosine kinase inhibitor resistance becoming a ubiquitous clinical problem. The identification of specific mechanisms of acquired resistance has allowed a better understanding of the biology and natural history of resistant disease, but is only now starting to impact treatment decisions. Strategies for managing acquired resistance in patients with advanced non-small cell lung cancer are complex and must be adapted to the individual characteristics of each patient's cancer. Although combination chemotherapy is the presumed standard of care for most patients, prospective trial data are lacking, highlighting the importance of offering patients participation in clinical trials in this setting. Emerging data from trials of third-generation mutant-specific EGFR kinase inhibitors suggests particular promise with this class of agents.

Effects of 4-nonylphenol and bisphenol A on stimulation of cell growth via disruption of the transforming growth factor-β signaling pathway in ovarian cancer models.

Abstract: Transforming growth factor β (TGF-β) signaling pathway is a major pathway in cellular processes such as cell growth, apoptosis, and cellular homeostasis. The signaling pathway activated by 17β-estadiol (E2) appeared to inhibit the TGF-β signaling pathway by cross-talk with the TGF-β components in estrogen receptor (ER) positive cells. In this study, we examined the inhibitory effects of endocrine disrupting chemicals (EDCs), including 4-nonylphenol (NP), 4-otylphenol (OP), bisphenol A (BPA), and benzophenon-1 (BP-1), in the TGF-β signaling pathway in BG-1 ovarian cancer cells expressing estrogen receptors (ERs). The transcriptional and translational levels of TGF-β related genes were examined by reverse transcription-PCR (RT-PCR), Western blot analysis, and xenograft mouse models of ovarian cancer cells. As a result, treatment with NP, OP, and BPA induced the expressions of SnoN, a TGF-β pathway inhibitor, and c-Fos, a TGF-β target transcription factor. Treatment with NP, BPA, and BP-1 resulted in decreased phosphorylation of Smad3, a downstream target of TGF-β. These results indicate that NP and BPA may stimulate the proliferation of BG-1 cells via inhibition of the TGF-β signaling pathway. In a xenograft mouse model, transplanted BG-1 ovarian cancer cells showed significantly decreased phosphorylation of Smad3 and increased expression of SnoN in the ovarian tumor masses following treatment with E2, NP, or BPA. In parallel with an in vitro model, the expressions of these TGF-β signaling pathway were similarly regulated by NP or BPA in a xenograft mouse model. These results support the fact that the existence of an unproven relationship between EDCs/ER-α and TGF-β signaling pathway and a further study are required in order to verify more profound and distinct mechanism(s) for the disturbance of the TGF-β signaling pathway by diverse EDCs.

The role of nerve growth factor and its receptors in tumorigenesis and cancer pain.

Abstract: The nerve growth factor (NGF) is a growth factor that belongs to the neurotrophin family. NGF has two structurally different receptors, the p75 neurotrophin receptor (p75NTR) and the tropomyosin-related kinase A (TrkA). Interaction of NGF with its receptors regulates a variety of physiological processes of neuronal system. Recent studies have shown that NGF and its receptors were involved in the regulation of tumourigenesis by either supporting or suppressing tumor growth depending on the tumor types. This review summarizes the current views of NGF and its receptors in tumorigenesis and cancer pain.

Growth and survival of lung cancer cells: regulation by kallikrein-related peptidase 6 via activation of proteinase-activated receptor 2 and the epidermal growth factor receptor.

Abstract: The dysregulated expression of kallikrein-related peptidase 6 (KLK6) is involved in non-small cancer (NSCLC) cell growth. However, the mechanism that sustains KLK6 signaling remains unknown. We used an isogenic non-small cell lung cancer (NSCLC) cell model system to demonstrate that KLK6 promotes the proliferation of lung tumoral cells and restrains their apoptosis in vitro via ligand-dependent EGFR transactivation. KLK6 activated the ERK and Akt pathways and triggered the nuclear translocation of β-catenin. The stimulating effects of KLK6 required its proteolytic activity and were dependent on the protease-activated receptor 2 (PAR2). These observations support the concept of a role for KLK6 in the oncogenesis of NSCLC.

FTY720 and cisplatin synergistically induce the death of cisplatin-resistant melanoma cells through the downregulation of the PI3K pathway and the decrease in epidermal growth factor receptor expression

Abstract: Sphingosine kinase (SK), a key enzyme in sphingosine-1-phosphate (S1P) synthesis, is known to be overexpressed in various types of cancer cells. The effects of anticancer agents on SK1/S1P signaling have not yet been fully assessed in melanoma cells. In the present study, we investigated the effects of the combination of FTY720, an S1P receptor antagonist, and cisplatin, a DNA-damaging agent, on the induction of the death of human melanoma cells, as well as the molecular mechanisms involved. The viability of various human melanoma cell lines was examined following treatment with anticancer drugs. The cisplatin-resistant SK-Mel-28 and cisplatin-sensitive A375 cell lines were selected for this analysis. Protein expression and apoptotic rates were evaluated by western blot analysis following treatment with cisplatin and/or FTY720. Following treatment with a combination of FTY720 and cisplatin, cell viability significantly decreased and the expression of apoptosis-associated cleaved poly(ADP-ribose) polymerase (PARP) was significantly higher in comparison to treatment with cisplatin alone in the SK-Mel-28 cells. In addition, the combination of FTY720 and cisplatin reduced the protein expression of SK1 and the phosphorylation levels of phosphoinositide 3-kinase (PI3K), Akt and mTOR in the SK-Mel-28 cells; the expression of epidermal growth factor receptor (EGFR) was also markedly reduced. These findings suggest that FTY720 and cisplatin synergistically induce cell death through the downregulation of the PI3K/Akt/mTOR pathway and the decrease in EGFR expression in SK-Mel-28 cells. Thus, the combination of FTY720 and cisplatin may have therapeutic potential for chemotherapy-resistant melanoma, and the effects are likely exerted through the downregulation of S1P signaling.

Combined gefitinib and pemetrexed overcome the acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Abstract: Currently, chemotherapy and targeted therapies share the principal limitation of the emergence of drug resistance, which prevents these strategies from having lasting clinical benefits. The combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with concurrent chemotherapy has been proposed as one strategy to overcome acquired resistance to EGFR-TKIs. The purpose of the present study was to investigate the combined effects of gefitinib and pemetrexed on EGFR-TKI-sensitive and EGFR‑TKI‑resistant human non-small cell lung cancer (NSCLC) cell lines. The antiproliferative effects of gefitinib and pemetrexed, alone and in combination, on the growth of NSCLC cell lines, were assessed using an MTT assay. The cytotoxic interaction between the two drugs was evaluated in vitro using the combination index (CI) method. Cell cycle distribution and apoptosis were analyzed by flow cytometry and alterations in signaling pathways were determined by western blot analysis. In the present study, it was identified that when cells were concurrently exposed to pemetrexed and gefitinib, cytotoxic synergism was present in the gefitinib-resistant PC9/GR human NSCLC cell line and antagonistic interactions were observed in the gefitinib-sensitive PC9 cell line. Synergism was associated with a combination of cell cycle effects of the different agents. In addition, the combination of pemetrexed and gefitinib decreased the levels of phosphorylated AKT, phosphorylated extracellular-signal-regulated kinase and B-cell lymphoma 2 as compared with those in the control. By contrast, antagonism was associated with gefitinib-induced G0/G1-phase blockade of gefitinib-sensitive cells, which interfered with the cell cycle-specific cytotoxicity of chemotherapy. The combination of pemetrexed and gefitinib generated synergistic effects in gefitinib-acquired resistant cells and antagonistic effects in gefitinib-sensitive cells, suggesting that EGFR-TKIs combined with pemetrexed may be a beneficial treatment strategy for NSCLC patients with acquired resistance to EGFR-TKIs.

Dovitinib synergizes with oxaliplatin in suppressing cell proliferation and inducing apoptosis in colorectal cancer cells regardless of RAS-RAF mutation status

Abstract: Cancer is the result of a multistep process of genomic alterations, including mutations in key regulatory proteins that result in loss of balanced gene expression and subsequent malignant transformation. Throughout the various stages of colorectal carcinoma (CRC), complex genetic alterations occur, of which over-expression of growth factors, such as vascular endothelial growth factor, fibroblast growth factor and platelet-derive growth factor and their corresponding receptor tyrosine kinases, have been shown to correlate with invasiveness, tumor angiogenesis, metastasis, recurrence, and poor prognosis of colorectal cancer. To evaluate the therapeutic effect, we combined Dovitinib, an orally bioavailable, potent inhibitor of class III-V receptor tyrosine kinases with chemotherapeutic drug, oxaliplatin in preclinical models of colon cancer. Human colon cancer cells with different RAS-RAF mutation status (HCT-116, HT-29, SW-480, CaCO2 and LS174T) were treated with a combination of Dovitinib and Oxaliplatin at low dosage followed by assays to investigate the effect of the combination on cell proliferation, cell migration, cell apoptosis and signaling pathways involved in molecular mechanism of drug(s). The antitumor effects of either of the drugs were compared to the combination using human colon carcinoma cell line HT-29 xenograft model. Treated vs untreated tumor sections were also compared for proliferation and angiogenesis markers by immunohistochemistry. The combination of dovitinib and oxaliplatin showed higher in vitro cytotoxicity in colon cell lines irrespective of their RAS-RAF status as compared to either of the drugs alone. Simultaneous inhibition of MAP kinase and AKT pathways and induction of apoptosis via activation of caspases 9/caspases 3 contributed to the synergistic effect of this combination therapy. In the xenograft model, the combination showed a significantly higher antitumor activity. Immunohistochemistry of post treatment tumors showed a significant decrease in proliferation and angiogenesis as compared to either of the treatments alone. This study demonstrates the synergistic antitumor activity of combination of dovitinib and oxaliplatin against colon cancer with different RAS-RAF status. The combination also showed its antitumor efficacy in a multidrug resistant phenotype xenograft model. This provides a basis for further investigation for its potential in clinical setting for colorectal cancer.

Transient antiangiogenic treatment improves delivery of cytotoxic compounds and therapeutic outcome in lung cancer

Abstract: Extensive oncologic experience argues that the most efficacious applications of antiangiogenic agents rely upon a combination with cytotoxic drugs. Yet there remains a lack of clarity about how to optimize scheduling for such drug combinations. Prudent antiangiogenic therapy might transiently normalize blood vessels to improve tumor oxygenation and drug exposure. Using [(15)O]H2O positron emission tomography imaging in a preclinical mouse model of non-small cell lung cancer, we observed that short-term treatment with the vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibitor PTK787 licensed a transient window of improved tumor blood flow. The improvement observed was associated with a reduced leakiness from tumor vessels, consistent with induction of a vascular normalization process. Initiation of a cytotoxic treatment in this window of tumor vessel normalization resulted in increased efficacy, as illustrated by improved outcomes of erlotinib administration after initial PTK787 treatment. Notably, intermittent PTK787 treatment also facilitated long-term tumor regression. In summary, our findings offer strong evidence that short-term antiangiogenic therapy can promote a transient vessel normalization process that improves the delivery and efficacy of a targeted cytotoxic drug.

The current state of molecularly targeted drugs targeting HGF/Met.

Abstract: Met is a tyrosine kinase that has hepatocyte growth factor as its ligand. Met plays a major role in cell growth, migration and morphological changes. Overexpression of hepatocyte growth factor and Met and mutations and amplification of MET have been noted in many forms of cancer and are reportedly correlated with cancer progression and a poor prognosis. Over the past few years, these molecules have attracted attention as targets of molecularly targeted therapies. This article describes the association relationship between hepatocyte growth factor/Met and cancer and it describes the latest findings regarding inhibitors to target hepatocyte growth factor/Met that are currently being developed.