Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II.

Cardiac hypertrophy is an important risk factor for heart failure. Epidermal growth factor receptor (EGFR) has been found to play a role in the pathogenesis of various cardiovascular diseases. The aim of this current study was to examine the role of EGFR in angiotensin II (Ang II)-induced cardiac hypertrophy and identify the underlying molecular mechanisms. In this study, we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B (AKT)/extracellular signal-regulated kinase (ERK), and then induce cell hypertrophy in H9c2 cells. Both pharmacological inhibitors and genetic silencing significantly reduced Ang II-induced EGFR signalling pathway activation, hypertrophic marker overexpression, and cell hypertrophy. In addition, our results showed that Ang II-induced EGFR activation is mediated by c-Src phosphorylation. In vivo, Ang II treatment significantly led to cardiac remodelling including cardiac hypertrophy, disorganization and fibrosis, accompanied by the activation of EGFR signalling pathway in the heart tissues, while all these molecular and pathological alterations were attenuated by the oral administration with EGFR inhibitors. In conclusion, the c-Src-dependent EGFR activation may play an important role in Ang II-induced cardiac hypertrophy, and inhibition of EGFR by specific molecules may be an effective strategy for the treatment of Ang II-associated cardiac diseases.

Dietary calcium supplementation enhances efficacy but also toxicity of EGFR inhibitor therapy for colon cancer.

The inverse correlation between levels of dietary calcium and colorectal cancer (CRC) incidence has been extensively investigated. However, the impact of supplemental calcium on cancer therapy remains unknown. We used four models of CRC, Caco-2 and HCT116 human cancer cell lines and Apc (Min/+) and azoxymethane carcinogen-induced mouse models, to investigate the impact of a western-style diet low in calcium (0.05%) vs. a similar diet but supplemented with calcium (5%) on therapeutic targeting of the epidermal growth factor receptor (EGFR). We found that calcium supplementation combined with pharmacologic blockade of EGFR results in an additive effect on tumor growth inhibition in all models. Unexpectedly, the combined use of dietary calcium supplementation and EGFR inhibitors also resulted in elevated toxicity suggesting that careful consideration be given when combining dietary supplements with prescribed cancer therapies.

Combined treatment of curcumin and small molecule inhibitors suppresses proliferation of A549 and H1299 human non-small-cell lung cancer cells.

Curcumin (diferuloylmethane) is a phenolic compound present in turmeric and is ingested daily in many parts of the world. Curcumin has been reported to cause inhibition on proliferation and induction of apoptosis in many human cancer cell lines, including non-small cell lung cancer cells (NSCLC). However, the clinical application of curcumin is restricted by its low bioavailability. In this report, it was observed that combined treatment of a low dosage of curcumin (5-10 µM) with a low concentration (0.1-2.5 µM) of small molecule inhibitors, including AG1478, AG1024, PD173074, LY294002 and caffeic acid phenethyl ester (CAPE) increased the growth inhibition in two human NSCLC cell lines: A549 and H1299 cells. The observation suggested that combined treatment of a low dosage of curcumin with inhibitors against epidermal growth factor receptor (EGFR), insulin-like growth factor 1 (IGF-1R), fibroblast growth factors receptor (FGFR), phosphatidylinositol 3-kinases (PI3K) or NF-κB signaling pathway may be a potential adjuvant therapy beneficial to NSCLC patients.

Role of epidermal growth factor gene in the development of pancreatic cancer and efficiency of inhibitors of this gene in the treatment of pancreatic carcinoma.

The expression of epidermal growth factor receptors in normal and tumor cells of the pancreas, the type and incidence of EGFR gene polymorphism were studied. EGFR gene expression in pancreatic adenocarcinoma cells significantly surpassed that in normal pancreatic cells. On the other hand, AA genome and A allele polymorphism in the EGF gene nucleotide pair G-A 61 is a significant risk factor for pancreatic cancer. The effect of AG-1478 preparation (a new-generation inhibitor of EGFR) on apoptosis and cell proliferation in pancreatic cancer was evaluated. This preparation is not inferior to 5FU by its apoptotic effect and significantly reduces cell proliferation, its antiproliferative effect being 1.5 times higher than that of 5FU.

Effects of high-affinity nerve growth factor receptor inhibitors on symptoms in the NC/Nga mouse atopic dermatitis model.

BACKGROUND: Nerve growth factor (NGF) is an important substance in the skin, where it modulates nerve maintenance and repair. However, the direct link between NGF and pruritic diseases such as atopic dermatitis is not yet fully understood. Our previous study showed that NGF plays an important role in the pathogenesis of atopic dermatitis-like skin lesions in NC/Nga mice. NGF mediates its effects by binding to two classes of transmembrane receptors, a high-affinity receptor (tropomyosin-related kinase A, TrkA) and a low-affinity receptor (p75). OBJECTIVES: To determine the significance of NGF receptors in the pathogenesis of atopic dermatitis, the effects of TrkA inhibitors AG879 and K252a on the symptoms of NC/Nga mice were evaluated. METHODS: Male NC/Nga mice with severe skin lesions were used. AG879 or K252a was applied to the rostral part of the back of mice five times a week. The dermatitis score for the rostral back was assessed once a week. The scratching behaviour was measured using an apparatus, MicroAct (Neuroscience, Tokyo, Japan). Immunofluorescence examinations were made in the rostral back skin for nerve fibres, NGF and TrkA receptor. RESULTS: Repeated applications of AG879 or K252a significantly improved the established dermatitis and scratching behaviour, and decreased nerve fibres in the epidermis. NGF was observed more weakly in keratinocytes, and a lower expression of TrkA was observed in stratum germinativum of the epidermis of mice treated with AG879 or K252a compared with those treated with vehicle. CONCLUSIONS: We suggest that NGF plays an important role in the pathogenesis of atopic dermatitis-like skin lesions via the high-affinity NGF receptor. These findings provide a new potential therapeutic approach for the amelioration of symptoms of atopic dermatitis.

Medicinal chemistry approaches to target the kinase activity of IGF-1R.

Various drug discovery approaches have been explored in recent years to modulate the function of insulin-like growth factor-1 receptor (IGF-1R). This article focuses on the contributions of low-molecular-mass inhibitors in the modulation of IGF-1R kinase activity, and provides an update on recent reviews for this type of agent. Different classes of compounds have been demonstrated to be capable of modulating the kinase activity of IGF-1R in ways that were not possible previously. Preclinical data with some of these inhibitors support the potential application of IGF-1R-targeted therapeutic strategies in the treatment of human cancers.

Inhibition of tyrosine kinase signaling after trauma-hemorrhage: a novel approach for improving organ function and decreasing susceptibility to subsequent sepsis.

OBJECTIVE: To determine whether administration of a tyrosine kinase inhibitor after trauma-hemorrhage has any beneficial effects on cardiovascular parameters and hepatocellular function and on survival rate after subsequent sepsis. BACKGROUND: Increased inflammatory cytokine release and concomitant activation of intracellular signaling pathways contributes to multiple organ dysfunction and increased susceptibility to subsequent sepsis after severe hemorrhagic shock. METHODS: Male Sprague-Dawley rats underwent a midline laparotomy (i.e., soft-tissue trauma induced) and were then bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringer's lactate. The rats were then resuscitated with four times the shed blood volume in the form of Ringer's lactate during a 60-minute period. A tyrosine kinase inhibitor, AG 556 (7.5 mg/kg), or vehicle was administered intraperitoneally at the middle of resuscitation. At 24 hours after resuscitation, various in vivo parameters such as heart performance, cardiac index, and hepatocellular function (i.e., the maximum velocity and the overall efficiency of indocyanine green clearance) were determined. Phosphorylation state of the mitogen-activated protein kinases p44/42 and p38 in the liver was assessed by Western blot analysis. In additional groups of rats, sepsis was induced by cecal ligation and puncture at 20 hours after hemorrhage. The necrotic cecum was excised 10 hours thereafter, and the survival rate was monitored for a period of 10 days. RESULTS: AG 556 treatment restored the depressed cardiovascular and hepatocellular functions after trauma-hemorrhage and resuscitation, which was associated with reduced phosphorylation of mitogen-activated protein kinases p44/42 and p38. Moreover, treatment with AG 556 significantly increased the survival rate of rats after trauma-hemorrhage and induction of subsequent sepsis compared with vehicle-treated rats. CONCLUSION: Inhibition of tyrosine kinase signaling after trauma-hemorrhage may represent a novel therapeutic approach for improving organ functions and decreasing the death rate from subsequent sepsis under such conditions.