A novel cytotoxic agent for human carcinoid tumors

Litvak, David A.; Papaconstantinou, Harry T.; Ko, Tien C.; Townsend, Courtney M.

doi:10.1067/msy.1998.91830

Cited by 6 publications

(4 citation statements)

References 20 publications

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“…The NaB-regulated increase of IGFBP-3 synthesis before growth arrest and apoptosis suggests that the regulation of IGFBP-3 expression could be another mechanism for NaB action, rather than an effect of treatment. This has also been suggested for other cell cycle-specific genes regulated by NaB and TSA including p21 Waf1/Cip1 , a cyclin cdk-inhibitor (41), p16 INK4 (38), p27 Kip1 (42), Rb protein (43), cyclin-D1 (44), Bcl-2 and Bax (45,46). It is apparent that the mechanism of action for NaB and TSA is multifactorial and may also include the regulation of IGFBP-3 synthesis and secretion.…”

Section: Discussionmentioning

confidence: 86%

Butyrate, a Histone Deacetylase Inhibitor, Activates the Human IGF Binding Protein-3 Promoter in Breast Cancer Cells: Molecular Mechanism Involves an Sp1/Sp3 Multiprotein Complex

et al. 2001

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Specific cell growth stimulators and inhibitors regulate IGF binding protein-3 (IGFBP-3), where in turn IGFBP-3 mediates their biological effects. The molecular mechanism(s) by which these factors regulate IGFBP-3 are unknown. Sodium butyrate, a histone deacetylase inhibitor causing growth arrest and differentiation, increases IGFBP-3 expression. We investigated the molecular mechanism of this induction using an IGFBP-3 promoter reporter system in MCF-7 and Hs578T breast cancer cells. IGFBP-3 promoter activity was induced up to 40-fold following a 24-h treatment with sodium butyrate and 46-fold in cells treated with trichostatin A, a pure histone deacetylase inhibitor. Deletion analysis of the IGFBP-3 promoter identified key sodium butyrate-responsive element(s) to a 45-bp region containing consensus binding sites for Sp1 and activating protein-2. Sp1 binding to the Sp1 site and Sp3 to the activating protein-2/GA-box played a functional role in sodium butyrate's activation of the IGFBP-3 promoter, however, with no change in binding direct sodium butyrate regulation was attributed to cofactors. The histone acetyltransferase p300 and histone deacetylase-1 were identified in multiprotein complexes containing DNA bound Sp1 and Sp3, with p300 accumulating following sodium butyrate treatment. Taken together, these data suggest that sodium butyrate increases IGFBP-3 expression by activating the IGFBP-3 promoter via an Sp1/Sp3 multiprotein complex, a mechanism that may be important for other key regulators of IGFBP-3.

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Section: Discussionmentioning

confidence: 86%

Butyrate, a Histone Deacetylase Inhibitor, Activates the Human IGF Binding Protein-3 Promoter in Breast Cancer Cells: Molecular Mechanism Involves an Sp1/Sp3 Multiprotein Complex

et al. 2001

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“…It is well documented that inhibition of the EGFR dependent pathway induces a perturbation of cell cycle progression and notably G1 arrest [34]. p21 and p27 are able to arrest the growth of cells in the G1 phase of the cell cycle [35]. The growth inhibitory effect induced by gefitinib in Ist-Mes-2 increased expression of both p27 and p21.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of gefitinib and rofecoxib in mesothelioma cells

Stoppoloni¹,

Canino²,

Cardillo³

et al. 2010

Mol Cancer

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BackgroundMalignant mesothelioma (MM) is an aggressive tumor that is resistant to conventional modes of treatment with chemotherapy, surgery or radiation. Research into the molecular pathways involved in the development of MM should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of MM. Combination of COX-2 and EGFR inhibitors, therefore, could be an effective strategy for reducing cell growth in those lines expressing the two molecular markers.ResultsIn order to verify the effect of COX-2 and EGFR inhibitors, five MM cell lines NCI-2452, MPP89, Ist-Mes-1, Ist-Mes-2 and MSTO-211 were characterized for COX-2 and EGFR and then treated with respective inhibitors (rofecoxib and gefitinib) alone and in combination. Only MPP89, Ist-Mes-1 and Ist-Mes-2 were sensitive to rofecoxib and showed growth-inhibition upon gefitinib treatment. The combination of two drugs demonstrated synergistic effects on cell killing only in Ist-Mes-2, the cell line that was more sensitive to gefitinib and rofecoxib alone. Down-regulation of COX-2, EGFR, p-EGFR and up-regulation of p21 and p27 were found in Ist-Mes-2, after treatment with single agents and in combination. In contrast, association of two drugs resulted in antagonistic effect in Ist-Mes-1 and MPP89. In these cell lines after rofecoxib exposition, only an evident reduction of p-AKT was observed. No change in p-AKT in Ist-Mes-1 and MPP89 was observed after treatment with gefitinib alone and in combination with rofecoxib.ConclusionsGefitinib and rofecoxib exert cell type-specific effects that vary between different MM cells. Total EGFR expression and downstream signalling does not correlate with gefitinib sensitivity. These data suggest that the effect of gefitinib can be potentiated by rofecoxib in MM cell lines where AKT is not activated.

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“…Autocrine stimulation of a carcinoid cell line by serotonin resulted in an increase of ODC1 activity and an induction of cellular proliferation [103]. Inhibition of ODC1 by alphadifluoromethylornithine (DFMO) slowed the growth of pancreatic carcinoid tumor cells in culture [104]. Similarly, DFMO-induced growth inhibition of medullary thyroid carcinoma cells in culture was observed and resulted in reduced synthesis of the peptide hormones calcitonin and calcitonin gene-related peptide (CGRP) [105].…”

Section: Polyamine Biosynthesismentioning

confidence: 93%

Current concepts in neuroendocrine cancer metabolism

Ippolito

2006

Pituitary

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Neuroendocrine (NE) cancers occur in multiple anatomic locations and range in prognosis from indolent to aggressive. In addition, adenocarcinomas can express gene products associated with NE cells, referred to as NE differentiation (NED), which correlates with poor prognosis and aggressive disease. Several metabolites and peptides produced by NE cells have been discovered that engage in cellular signaling and have autocrine and paracrine effects on cancer cell proliferation. This review focuses on the current knowledge of small molecule metabolism in NE cancers involving the synthesis of biogenic amine, polyamine, and amino acid neurotransmitters. Systems biology-directed approaches to NE cancer metabolism using gene expression profiling, liquid chromatography/mass spectrometry (LC/MS) and nuclear magnetic resonance (NMR) are also discussed. Furthermore, knowledge of metabolic and signaling pathways in NE cancers has led to the successful implementation of therapeutic regimens in cell culture and animal models of NE carcinogenesis.

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A novel cytotoxic agent for human carcinoid tumors

Cited by 6 publications

References 20 publications

Butyrate, a Histone Deacetylase Inhibitor, Activates the Human IGF Binding Protein-3 Promoter in Breast Cancer Cells: Molecular Mechanism Involves an Sp1/Sp3 Multiprotein Complex

Butyrate, a Histone Deacetylase Inhibitor, Activates the Human IGF Binding Protein-3 Promoter in Breast Cancer Cells: Molecular Mechanism Involves an Sp1/Sp3 Multiprotein Complex

Synergistic effect of gefitinib and rofecoxib in mesothelioma cells

Current concepts in neuroendocrine cancer metabolism

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