OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1.

Cancer cells develop protective adaptations against oxidative DNA damage, providing a strong rationale for targeting DNA repair proteins. There has been a high degree of recent interest in inhibiting the mammalian Nudix pyrophosphatase MutT Homolog 1 (MTH1). MTH1 degrades 8-oxo-dGTP, thus limiting its incorporation into genomic DNA.

The Existence of MTH1-independent 8-oxodGTPase Activity in Cancer Cells as a Compensatory Mechanism against On-target Effects of MTH1 Inhibitors.

Investigations into the human 8-oxodGTPase, MutT Homolog 1 (MTH1), have risen sharply since the first-in-class MTH1 inhibitors were reported to be highly tumoricidal. However, MTH1 as a cancer therapeutic target is currently controversial because subsequently developed inhibitors did not exhibit similar cytotoxic effects. Here, we provide the first direct evidence for MTH1-independent 8-oxodGTPase function in human cancer cells and human tumors, using a novel ATP-releasing guanine-oxidized (ARGO) chemical probe.

Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer.

Androgen deprivation (AD) therapy failure leads to terminal and incurable castration-resistant prostate cancer (CRPC). We show that the redox-protective protein thioredoxin-1 (TRX1) increases with prostate cancer progression and in androgen-deprived CRPC cells, suggesting that CRPC possesses an enhanced dependency on TRX1. TRX1 inhibition via shRNA or a phase I-approved inhibitor, PX-12 (untested in prostate cancer), impedes the growth of CRPC cells to a greater extent than their androgen-dependent counterparts.

MTH1 as a Chemotherapeutic Target: The Elephant in the Room.

Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated ROS levels, many tumors develop adaptive responses, such as enhanced redox-protective or oxidatively-generated damage repair pathways.

Actual exclusive breastfeeding rates and determinants among a cohort of children living in Gampaha district Sri Lanka: A prospective observational study.

Background: Exclusive breastfeeding (EBF) during the early months of life reduce infant morbidity and mortality. Current recommendation in Sri Lanka is to continue exclusive breastfeeding up to six months of age. Exclusive breastfeeding rates are generally assessed by the 24 recall method which overestimates the actual rates.

Comparative gene expression profiling of human umbilical vein endothelial cells and ocular vascular endothelial cells.

Background/aims: To investigate the difference between human umbilical vein endothelial cells (HUVEC) and human ocular microvascular endothelial cell (MVEC) gene expression, and to determine if these differences could improve the understanding of ocular angiogenic diseases.

Methods: The gene expression profiles of HUVEC and matched unpassaged human choroidal, retinal and iris endothelial cells were conducted using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays.

Comparison of choroidal and retinal endothelial cells: characteristics and response to VEGF isoforms and anti-VEGF treatments.

Neovascular eye diseases such as wet age-related macular degeneration and proliferative diabetic retinopathy are two of the most common causes of irreversible visual loss. Although mediated by vascular endothelial growth factor (VEGF), the mechanisms of these diseases are not fully understood. Molecular inhibitors of VEGF including pegaptanib, ranibizumab and bevacizumab are used as treatments for these diseases.

Modified taxols, 9. Synthesis and biological evaluation of 7-substituted photoaffinity analogues of taxol.

The 7-substituted taxol analogues 7, 19, 27, and 32 have been prepared as potential photoaffinity-labeled derivatives for studies of the nature of the binding site of taxol on polymerized tubulin. The analogue 32 has been prepared in both deuterium- and tritium-labeled versions. Tubulin-assembly studies were carried out with these compounds, and it was found that they showed some but not all of the properties of taxol.

Modified taxols, 8. Deacylation and reacylation of baccatin III.

Hydrogenation of baccatin III over platinum converted it to its hexahydro derivative, and deacylation of this as its 7-triethylsilyl derivative was achieved with methoxide ion. The 10-acetate was hydrolyzed first, followed by the C-4 acetate and then the C-2 cyclohexylcarboxylate; an explanation for this unexpected order is presented. Base treatment also yielded a rearranged analogue with a tetrahydrofuran ring in place of the oxetane ring of baccatin III.

Bioactive ergost-5-ene-3 beta, 7 alpha-diol derivatives from Pseudobersama mossambicensis.

Bioactivity-directed fractionation of the methyl ethyl ketone extract of Pseudobersama mossambicensis resulted in the isolation of ergosta-5,24(28)-diene-3 beta,7 alpha-diol [1], 24,28-epoxyergost-5-ene-3 beta,7 alpha-diol [2], and ergost-5-ene-3 beta,7 alpha,24,28-tetraol [3]. All three sterols showed selective activity towards DNA repair-deficient yeast mutants. The sterol 1 also showed cytotoxicity towards wild-type P-388 murine leukemia cells.