Oxidative Stress, Inflammation, and Cancer: How Are They Linked?

The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.

Wnt signalling in stem cells and cancer

Signaling--2000 and beyond.

Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.

https://science.sciencemag.org/content/sci/305/5682/399.full.pdf

Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor

We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide) Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor We also expressed a Gi-coupled designer receptor in hippocampal neurons (hM4D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo

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Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand

A series of 3,5-disubstituted-1,2,4-oxadiazoles were synthesized and evaluated for their in vitro anti-proliferative activities against various cancer cell lines. Formation of 1,2,4-oxadiazole ring was accomplished by the reaction of amidoxime with carboxylic acids. The in vitro cytotoxic effects of 3,5-disubstituted-1,2,4-oxadiazoles have been demonstrated across a wide array of tumor cell types and a few compounds exhibited specificity towards pancreatic (3f, 3h, 3j, and 3k) and prostate (3n) cancer cells. Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 3n is the most selective (>450-fold) and compound 3p is the most cytotoxic (10 nM) against prostate cancer cell lines.

Synthesis and Anticancer Activities of Novel 3,5-Disubstituted-1,2,4-oxadiazoles.

Sequential one-pot synthesis of bis(indolyl)glyoxylamides: Evaluation of antibacterial and anticancer activities.

Engineering unnatural nucleotide specificity to probe G protein signaling.

Replication of human immunodeficiency virus type 1 (HIV-1) requires specific interactions of Tat protein with the trans-activation responsive region (TAR) RNA, a 59-base stem−loop structure located at the 5‘-end of all HIV mRNAs. We have used a site-specific cross-linking method based on psoralen photochemistry to determine the effect of core residues from the Tat sequence on the protein orientation in the Tat−TAR complex and on the specificity of Tat−TAR binding. We synthesized two Tat fragments, Tat(42−72) and Tat(37−72), and incorporated a psoralen-modified amino acid at position 41 during solid-phase assembly of the peptides. We used these psoralen−Tat conjugates to form specific complexes with TAR RNA. Upon near-ultraviolet irradiation (360 nm), psoralen−Asp41−Tat(37−72) cross-linked to a single site in the TAR RNA sequence. The RNA−protein complex was purified and the cross-link site on TAR RNA was determined by primer extension analysis, which revealed that Asp41 of Tat is close to U42 of the lower...

Kavita Shah

Papers

Synthesis and Anticancer Activities of Novel 3,5-Disubstituted-1,2,4-oxadiazoles.

Sequential one-pot synthesis of bis(indolyl)glyoxylamides: Evaluation of antibacterial and anticancer activities.

Engineering unnatural nucleotide specificity to probe G protein signaling.

Probing Tat peptide-TAR RNA interactions by psoralen photo-cross-linking.

A single amino-acid change in ERK1/2 makes the enzyme susceptible to PP1 derivatives.