EGF Receptors of Hepatocytes from Rats Treated with Phenobarbital Are Sensitized to Down-Regulation by Phenobarbital in Culture

Dalton, Shana R.; Jirtle, Randy L.; Meyer, Sharon A.

doi:10.1006/taap.2000.8935

Cited by 8 publications

(4 citation statements)

References 72 publications

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“…To test this hypothesis, we assessed whether gefitinib influences the proliferation of cells that do not rely on the EGFR for proliferation. We used two human cancer cell lines: the human hepatocellular carcinoma line HepG2, which expresses very low levels of EGFR, 42 and a doxorubicin-resistant SKNSH neuroblastoma line, which does not express detectable levels of EGFR. 43 Concentrations of 5 and 10 μM gefitinib significantly reduced HepG2 proliferation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Suppression of proliferation of two independent NF1 malignant peripheral nerve sheath tumor cell lines by the pan-ErbB inhibitor CI-1033

Dilworth

Wojtkowiak

Mathieu

et al. 2008

Cancer Biology & Therapy

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Neurofibromatosis Type 1 (NF1) is characterized by the abnormal proliferation of neuroectodermal tissues and the development of certain malignancies, particularly neurofibromas, which may progress into malignant peripheral nerve sheath tumors (MPNSTs). Effective pharmacological therapy for the treatment of NF1 tumors is currently unavailable, and the prognosis for patients with MPNSTs is poor. Loss of neurofibromin correlates with increased expression of the epidermal growth factor receptor (EGFR) and ErbB2 tyrosine kinases, and these kinases have been shown to promote NF1 tumor-associated pathologies in vivo. We show here that while NF1 MPNST cells have higher EGFR expression levels and are more sensitive to EGF when compared to a non-NF1 MPNST cell line, the ability of the EGFR inhibitor gefitinib to selectively inhibit NF1 MPNST cell proliferation is marginal. We also show that NF1 MPNST proliferation correlates with activated ErbB2, and can be suppressed by nanomolar concentrations of the pan-ErbB inhibitor CI-1033 (canertinib). Consequently, targeting both EGFR and ErbB2 may prove an effective strategy for suppressing NF1 MPNST tumor growth in vivo.

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Section: Resultsmentioning

confidence: 99%

Suppression of proliferation of two independent NF1 malignant peripheral nerve sheath tumor cell lines by the pan-ErbB inhibitor CI-1033

Dilworth

Wojtkowiak

Mathieu

et al. 2008

Cancer Biology & Therapy

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“…Exposure duration of 14 days was used because this was the earliest interim time point at which serum TSH was increased by 0.5 mmol/kg/day alachlor in the study of Wilson et al (1996). Positive-control PB was given in drinking water by supplementing at 0.1% w/v, a protocol estimated to deliver 0.5 mmol/kg/day and previously shown to induce CYP2B1/2 expression (Dalton, Jirtle, and Meyer 2000). Exposure for 14 days to comparable PB dosages in the diet (McClain et al 1989) or by gavage (O'Connor, Frame, and Ladics 2002) has been shown to increase thyroid weight and incidence of follicular cell hypertrophy, and also alter serum T 3 , T 4 , and TSH levels.…”

Section: Animal Husbandry and Treatmentmentioning

confidence: 99%

The Herbicide Metolachlor Induces Liver Cytochrome P450s 2B1/2 and 3A1/2, but Not Thyroxine-Uridine Dinucleotide Phosphate Glucuronosyltransferase and Associated Thyroid Gland Activity

2003

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Metolachlor (2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamide) is widely used internationally as a corn and cotton herbicide. The metolachlor effects noted in rats during testing for U.S. pesticide registration include increased liver weight and hepatocarcinogenicity associated with eosinophilic foci. These properties, plus nongenotoxicity, are also characteristic of the prototypical rat liver tumor promoter, phenobarbital. Phenobarbital induces hepatic cytochrome P450s CYP2B1/2 and CYP3A1/2 and thyroxine (T(4))-UDP-glucuronosyltransferase (T(4)-UGT), which enhances thyroxine clearance and thus indirectly increases thyroid gland activity. Because other chloroacetanilide herbicides are known to similarly affect rat thyroid gland, this study tested the hypothesis that metolachlor would have these additional phenobarbital-like effects on liver, especially that of T(4)-UGT induction with consequential stimulation of thyroid gland. Effects of metolachlor, fed to male Sprague-Dawley rats for 14 days at the carcinogenic dose of 3000 ppm, were compared to those of equimolar phenobarbital. Liver microsomal CYP2B1/2 and CYP3A1/2 were probed by immunoblotting and T(4)-UGT was measured enzymatically. Serum T(4), triiodothyronine (T(3)), and thyroid-stimulating hormone (TSH) and thyroid follicular epithelial cell morphology and proliferation were used to assess thyroid gland activity. Metolachlor induced CYP2B1/2 and CYP3A1/2 proteins, but unlike phenobarbital, did not affect T(4)-UGT activity. In agreement, serum T(4), T(3), or TSH were unaffected by metolachlor. Also, no significant effects of metolachlor on thyroid gland morphology or follicular epithelial cell height or proliferation were observed. These data demonstrate that metolachlor is an inducer of hepatic CYP2B1/2 activity. But unlike the prototypical CYP2B1/2 inducer phenobarbital, metolachlor does not cause an increase in T(4)-glucuronidation and thyroid gland activation.

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“…1) has been used widely as a sedative and hypnotics agent in the short-term treatment of insomnia and preoperatively to relieve anxiety and provide sedation [8][9][10]. Many researches indicated that the mechanism of action of barbital was to act an g-aminobutyric acid receptor (GABA receptor) [11,12] and influences conductions at the chloride channel coupled with GABA receptor [8,13]. So barbital has strong inhibiting effect on the central nervous system [11].…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic studies on the binding of barbital to bovine serum albumin

Ding

Pan

et al. 2009

Journal of Luminescence

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EGF Receptors of Hepatocytes from Rats Treated with Phenobarbital Are Sensitized to Down-Regulation by Phenobarbital in Culture

Cited by 8 publications

References 72 publications

Suppression of proliferation of two independent NF1 malignant peripheral nerve sheath tumor cell lines by the pan-ErbB inhibitor CI-1033

Suppression of proliferation of two independent NF1 malignant peripheral nerve sheath tumor cell lines by the pan-ErbB inhibitor CI-1033

The Herbicide Metolachlor Induces Liver Cytochrome P450s 2B1/2 and 3A1/2, but Not Thyroxine-Uridine Dinucleotide Phosphate Glucuronosyltransferase and Associated Thyroid Gland Activity

Spectroscopic studies on the binding of barbital to bovine serum albumin

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