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Your search keyword '"Janet Weinstock"' showing total 2 results
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2 results on '"Janet Weinstock"'

1. Dual drug targeting to kill colon cancers

Author

Silvia Paola Corona, Francesca Walker, Janet Weinstock, Guillaume Lessene, Maree Faux, and Antony W. Burgess

Subjects
adenoma, apoptosis, pro‐survival inhibitors, signaling, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Introduction Colorectal cancer (CRC) is driven by a small set of oncogenic and tumour suppressor mutations. However, different combinations of mutations often lead to poor tumour responses to individual anticancer drugs. We have investigated the antiproliferative and in vitro cytotoxic activity of pair‐wise combinations of inhibitors which target specific signalling pathways in colon cancer cells. Objectives To target specific signaling pathways pairwise with inhibitors in order to kill colon cancer cells. Methods The effects of different concentrations of two inhibitors on the proliferation and viability of colon cancer cell lines were measured using cell titre glow and cytotoxic assays in 2D and 3D cell micro‐cultures. One successful drug combination was used to treat a colon cancer cell line growing as a xenograft in nude mice. Results Colon cancer cells in non‐adherent cultures were killed more effectively by combinations of pyrvinium pamoate (a Wnt pathway inhibitor) and ABT263 (a pro‐apoptotic Bcl‐2 family inhibitor) or Ly29004 (a PI3kinase inhibitor). However, in a mouse xenograft model, the formulation and toxicity of the ABT737/PP combination prevent the use of these drugs for treatment of tumours. Fortunately, oral analogues of PP (pyrvinium phosphate, PPh) and ABT737(ABT263) have equivalent activity and can be used for treatment of mice carrying SW620 colorectal cancer xenografts. The PPh/ABT263 induced SW620 tumour cell apoptosis and reduced the rate of SW620 tumour growth. Conclusion By combining a Wnt signaling inhibitor (pyrvinium phosphate) and a pro‐survival inhibitor (ABT263) colon cancer cells can be killed. Combinations of Wnt signalling inhibitors with an inhibitor of the Bcl pro‐survival protein family should be considered for the treatment of patients with precancerous colon adenomas or advanced colorectal cancers with APC mutations.

Published
2022
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2. Structure-Function analysis of human IL-6: Identification of two distinct regions that are important for receptor binding

Author

Larry D. Ward, Richard J. Simpson, Herbert R. Treutlein, Annet Hammacher, Janet Weinstock, and Kiyoshi Yasukawa

Subjects
Models, Molecular, Carcinoma, Hepatocellular, Molecular model, Protein Conformation, Recombinant Fusion Proteins, Biosensing Techniques, Biology, Lymphocyte Activation, Binding, Competitive, Biochemistry, Mice, Structure-Activity Relationship, Species Specificity, Granulocyte Colony-Stimulating Factor, Tumor Cells, Cultured, Animals, Humans, Bioassay, Amino Acid Sequence, Homology modeling, Receptor, Molecular Biology, Base Sequence, Sequence Homology, Amino Acid, Interleukin-6, Circular Dichroism, Liver Neoplasms, Fibrinogen, Biological activity, Receptors, Interleukin, Receptors, Interleukin-6, Molecular biology, Cell biology, Restriction enzyme, Cell culture, Helix, Multiple Myeloma, Sequence Alignment, Research Article, Protein Binding
Abstract

Interleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in host defense. It has been predicted that IL-6 may fold as a 4 alpha-helix bundle structure with up-up-down-down topology. Despite a high degree of sequence similarity (42%) the human and mouse IL-6 polypeptides display distinct species-specific activities. Although human IL-6 (hIL-6) is active in both human and mouse cell assays, mouse IL-6 (mIL-6) is not active on human cells. Previously, we demonstrated that the 5 C-terminal residues of mIL-6 are important for activity, conformation, and stability (Ward LD et al., 1993, Protein Sci 2:1472-1481). To further probe the structure-function relationship of this cytokine, we have constructed several human/mouse IL-6 hybrid molecules. Restriction endonuclease sites were introduced and used to ligate the human and mouse sequences at junction points situated at Leu-62 (Lys-65 in mIL-6) in the putative connecting loop AB between helices A and B, at Arg-113 (Val-117 in mIL-6) at the N-terminal end of helix C, at Lys-150 (Asp-152 in mIL-6) in the connecting loop CD between helices C and D, and at Leu-178 (Thr-180 in mIL-6) in helix D. Hybrid molecules consisting of various combinations of these fragments were constructed, expressed, and purified to homogeneity. The conformational integrity of the IL-6 hybrids was assessed by far-UV CD. Analysis of their biological activity in a human bioassay (using the HepG2 cell line), a mouse bioassay (using the 7TD1 cell line), and receptor binding properties indicates that at least 2 regions of hIL-6, residues 178-184 in helix D and residues 63-113 in the region incorporating part of the putative connecting loop AB through to the beginning of helix C, are critical for efficient binding to the human IL-6 receptor. For human IL-6, it would appear that interactions between residues Ala-180, Leu-181, and Met-184 and residues in the N-terminal region may be critical for maintaining the structure of the molecule; replacement of these residues with the corresponding 3 residues in mouse IL-6 correlated with a significant loss of alpha-helical content and a 200-fold reduction in activity in the mouse bioassay. A homology model of mIL-6 based on the X-ray structure of human granulocyte colony-stimulating factor is presented.

Published
1994
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