Supplementary Data from Establishment and Characterization of a Model of Acquired Resistance to Epidermal Growth Factor Receptor Targeting Agents in Human Cancer Cells
Sergio BenaventeShyhmin HuangEric A. ArmstrongAlexander ChiKun-Tai HsuDeric L. WheelerPaul M. Harari
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Supplementary Data from Establishment and Characterization of a Model of Acquired Resistance to Epidermal Growth Factor Receptor Targeting Agents in Human Cancer CellsCite
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Platelet-derived growth factor does not compete with epidermal growth factor (EGF) for binding to EGF receptors on the murine 3T3 cell surface, but it modulates EGF receptors in two ways: (i) it induces a transient down regulation of EGF receptors and (ii) it inhibits EGF-induced down regulation of EGF receptors. These data suggest a common cellular internalization mechanism for the receptors for both hormones.
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Abstract: The signal transduction and cell proliferation are regulated by the epidermal growth factor receptor. The proliferation of tumor cells, apoptosis, invasion, and angiogenesis is inhibited by the epidermal growth factor receptor. Thus, breast cancer, non-small cell lung cancer, cervical cancer, glioma, and bladder cancer can be treated by targeting the epidermal growth factor receptor. Although third-generation epidermal growth factor receptor inhibitors are potent drugs, patients exhibit drug resistance after treatment. Thus, the search for new drugs is being continued. Among the different potent epidermal growth factor receptor inhibitors, we have reviewed the indole-based inhibitors. We have discussed the structure-activity relationship of the compounds with the active sites of the epidermal growth factor receptor receptors, their synthesis, and molecular docking studies.
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PC12 cells possess specific receptors for both nerve growth factor and epidermal growth factor, and by an unknown mechanism, nerve growth factor is able to attenuate the propagation of a mitogenic response to epidermal growth factor. The differentiation response of PC12 cells to nerve growth factor, therefore, predominates over the proliferative response to epidermal growth factor. We have observed that the addition of nerve growth factor to PC12 cells rapidly produces a decrease in surface 125I-epidermal growth factor binding capacity. Unlike previously described nerve growth factor effects on 125I-epidermal growth factor binding capacity, which required several days of nerve growth factor exposure, the decreases we report occur within minutes of nerve growth factor addition: A 50% decrease in 125I-epidermal growth factor binding capacity is evident at 10 min. This rapid nerve growth factor response is concentration dependent; inhibition of 125I-epidermal growth factor binding is detectable at nerve growth factor levels as low as 0.2 ng/ml and is maximal at approximately 50 ng/ml, consistent with known ranges of biological activity. No demonstrable differences in the rate of epidermal growth factor receptor synthesis or degradation were observed in cells acutely exposed to nerve growth factor. Scatchard analysis revealed that acute nerve growth factor treatment decreased the number of both high- and low-affinity 125I-epidermal growth factor binding sites, while the receptor affinity remained unchanged. We have also investigated the involvement of various potential intracellular mediators of nerve growth factor action and of known intracellular modulatory systems of the epidermal growth factor receptor for their capacity to participate in this nerve growth factor activity.
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PC12 cells, which differentiate morphologically and biochemically into sympathetic neruonlike cells in response to nerve growth fact, also respond to epidermal growth factor. The response to epidermal growth factor is similar in certain respects to the response to nerve growth fact. Both peptides produce rapid increases in cellular adhesion and 2-deoxyglucose uptake and both induce ornithine decarboxylase. But nerve growth factor causes a decreased cell proliferation and a marked hypertrophy of the cells. In contrast, epidermal growth factor enhances cell proliferation and does not cause hypertrophy. Nerve growth factor induces the formation of neuritis; epidermal growth factor does not. When both factors are presented simultaneously, the cells form neurites. Furthermore, the biological response to epidermal growth fact, as exemplified by the induction of ornithine decarboxylase, is attenuated by prior treatment of the cells with nerve growth factor. PC12 cells have epidermal growth factor receptors. The binding of epidermal growth factor to these receptors is rapid and specific, and exhibits an equilibrium constant of 1.9 x 10(-9) M. Approximately 80,000 receptors are present per cell, and this number is independent of cell density. Treatment of the cells with nerve growth factor reduces the amount of epidermal growth factor binding by at least 80 percent. The decrease in receptor binding begins after approximately 12-18 h of nerve growth factor treatment and is complete within 3 d. Scratchard plots indicate that the number of binding sites decreases, not the affinity of the binding sites for epidermal growth factor.
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Epidermal growth factor receptor inhibitors are the research focus in the molecular targeted therapy of lung cancer. Epidermal growth factor receptor inhibitors have been widely used for the treatment of non-small cell lung cancer. In recent years, it has been found that epidermal growth factor receptor mutation and its inhibitors are closely related to the clinical efficacy. This article reviews the research progress of epidermal growth factor receptor inhibitors and its mutation in the therapy of lung cancer.
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Epidermal growth factor receptor; Gene mutation; Lung cancer
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A431 cells
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In this report, we have studied the effect of epidermal growth factor (EGF) on the proliferation of breast cancer cell lines, as well as the modulation of estrogen -and epidermal growth factor - receptor levels by EGF treatment. We have observed that all the cell lines analysed were stimulated by EGF in low serum containing media. The MCF-7AZ cell line, its H-ras transfected MCF-7AZ TD5 variant and the MCF-7 cells, all of them containing a relatively low number of epidermal growth factor receptors, were growth stimulated in a dose-dependent manner by 10(-9) M to 10(-8) M EGF. The MDA-MB 231, A431 and BT20 cell lines that express higher receptor levels were stimulated with relatively low concentrations of epidermal growth factor (5 x 10(-13) M to 10(-11) M). However, A431 and BT20 cells were shown to be growth-inhibited in the presence of higher EGF concentrations (10(-10) M to 10(-8) M). We also observed that EGF down-regulated epidermal growth factor receptor while it up-regulated estrogen receptor. In addition, Scatchard analysis of radiolabeled EGF binding on cell surface demonstrated that the concentrations of growth factor necessary to occupy a given number of epidermal growth factor receptors are inversely correlated with the total level of these receptors. Our findings suggest that the mitogenic effect of epidermal growth factor on cell proliferation is a function of the quantity of EGF-occupied receptors.
A431 cells
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