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.

Thioredoxin (Trx) is a small redox-active protein that provides reducing equivalents for key cysteine residues of proteins through thiol-disulfide exchange, such as the transcription factor nuclear factor-κB (NF-κB). NF-κB activation has been associated previously with cell growth and the inhibition of apoptosis. We have shown in earlier studies that overexpression of Trx in MCF-7 cells increases anchorage-independent growth. In this study, the activation of NF-κB was examined as a mechanism through which Trx overexpression might promote anchorage-independent growth. Constitutive NF-κB activity is elevated 4–7-fold in Trx-overexpressing cells. NF-κB activity was inhibited in these cells by expressing a dominant-negative mutant of the IκBα protein (IκBαM). Expression of IκBαM in Trx-overexpressing cells dramatically reduced the Trx-associated increase in NF-κB activity but did not affect anchorage-dependent or -independent growth. The results suggest that increased growth in MCF-7 cells overexpressing Trx is not mediated by increased activation of the transcription factor, NF-κB. Additionally, activator protein-1 (AP-1), another transcription factor associated with growth, was increased up to 10-fold in Trx-overexpressing cells. Thus, AP-1 activation might contribute to the growth-promoting effect of Trx.

https://cancerres.aacrjournals.org/content/canres/59/16/4090.full.pdf

Nuclear Factor κB Transactivation Is Increased But Is Not Involved in the Proliferative Effects of Thioredoxin Overexpression in MCF-7 Breast Cancer Cells

Mechanism-based inhibition of thioredoxin reductase by antitumor quinoid compounds.

Inhibition of cellular thioredoxin reductase by diaziquone and doxorubicin. Relationship to the inhibition of cell proliferation and decreased ribonucleotide reductase activity.

Garth Powis

Papers

Nuclear Factor κB Transactivation Is Increased But Is Not Involved in the Proliferative Effects of Thioredoxin Overexpression in MCF-7 Breast Cancer Cells

Mechanism-based inhibition of thioredoxin reductase by antitumor quinoid compounds.

Inhibition of cellular thioredoxin reductase by diaziquone and doxorubicin. Relationship to the inhibition of cell proliferation and decreased ribonucleotide reductase activity.

Signalling pathways as target for anticancer drug development

Pharmacokinetics of anticancer agents in humans