https://staff.blog.ui.ac.id/hsuryadi/files/2012/02/ROS_RNS.pdf

Free radicals and antioxidants in normal physiological functions and human disease

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

Targeting HIF-1 for cancer therapy

Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.

Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?

If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.

Why do cancers have high aerobic glycolysis

http://www.healthcare.uiowa.edu/corefacilities/esr/publications/buettnerpubs/pdf/FRBM-2001-30-1191-FQS-Redox.pdf

Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.

Staurosporine inhibition of intracellular free Ca2+ transients in mitogen-stimulated Swiss 3T3 fibroblasts.

Enhanced formation of ethane and n-pentane by rat hepatocytes in the presence of dimethyl sulfoxide.

A comment on the absence of calcium regulation of human thioredoxin reductase

A U.S. National Cancer Institute screening program for new anticancer drugs, based on the growth of primary human tumor cells in an in vitro soft agar colony formation assay, has resulted in the identification of a number of compounds that have cytotoxic activity against primary human tumor cells in vitro but are inactive in the conventional in vivo murine P388 leukemia animal model pre-screen. To investigate whether metabolic inactivation ov the compounds might be a factor in the lack of in vivo cytotoxicity we have co-cultured rat hepatocytes with A204 rhabdomyosarcoma and murine P388 leukemia cell lines in the soft agarose colony formation assay for 24 h during exposure to the compounds. Twenty compounds with a range of in vitro activities were studied. Thirteen compounds exhibited cytotoxicity against A204 cells in culture; nine of them were less active when co-cultured with hepatocytes, two were activated by hepatocyte co-culture, and two showed no effect of hepatocyte co-culture. P388 cells were more sensitive to the antiproliferative effects of the compounds than A204 cells. Two compounds that were not active against A204 cells exhibited cytotoxicity against P388 cells. One compound was inactivated by hepatocyte co-culture and one showed no effect. Five compounds showed no cytotoxicity toward either A204 cells or P388 cells. Two of the compounds showing hepatocyte inactivation in vitro possess activity in one or more in vivo tumor models. Thus, evidence for metabolic inactivation in hepatocyte co-culture is not always an indication for lack of in vivo antitumor activity. Hepatocyte co-culture methodology provides a simple and objective means, amenable to large-scale screening, of distringuishing metabolic activation or inactivation of a given compound from other pharmacokinetic and pharmacodynamic factors with a minimum of material.

Metabolic stability of experimental chemotherapeutic agents in hepatocyte: tumor cell co-cultures

The pharmacokinetics and metabolism of sulfamic acid diester were studied in the beagle dog and mouse. Elimination of sulfamic acid diester from the plasma and whole blood following i.v. administration at a dose of 193 mg/m2 was best approximated by a three-compartment model in both species. The compound was relatively rapidly cleared from the plasma, with a plasma beta half-life of 2.3 h and 0.9 h and a gamma half-life of 16 h and 3 h in the dog and the mouse, respectively. Sulfamic acid diester was taken up by blood cells and only slowly eliminated with a whole blood gamma half-life of 42 h in the dog and 32 h in the mouse. When sulfamic acid diester was infused i.v. to mice at 15 mg/kg over 8 h, the clearance for the parent drug was 13.2 ml/min kg from the plasma and 3.3 ml/min kg from the whole blood. Urine collected from mouse and dog contained the parent drug and three metabolic/breakdown products, namely, sulfamic acid 1,7-heptanemonoyl ester, sulfamic acid 3-hydroxyl-1,7-heptanediyl ester, and an unidentified product. Excretion of unchanged drug and products in mouse urine over 8 h accounted for less than 16% of the dose of sulfamic acid diester. Sulfamic acid diester did not react with glutathione in buffer, whole blood, or 100 000 g rat liver cytosol.

Garth Powis

Papers

Staurosporine inhibition of intracellular free Ca2+ transients in mitogen-stimulated Swiss 3T3 fibroblasts.

Enhanced formation of ethane and n-pentane by rat hepatocytes in the presence of dimethyl sulfoxide.

A comment on the absence of calcium regulation of human thioredoxin reductase

Metabolic stability of experimental chemotherapeutic agents in hepatocyte: tumor cell co-cultures

Pharmacokinetics and metabolism of the antitumor agent sulfamic acid 1,7-heptanediyl ester (sulfamic acid diester) in the mouse and beagle dog.