Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.10119

Cellular response to oxidative stress: signaling for suicide and survival.

A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin

The identification and cloning of a segment of a human multidrug resistance gene (mdr1) was reported recently. To examine the molecular basis of one type of multidrug resistance, we have prepared RNA from human tumors and normal tissues and measured their content of mdr1 RNA. We find that the mdr1 gene is expressed at a very high level in the adrenal gland; at a high level in the kidney; at intermediate levels in the lung, liver, lower jejunum, colon, and rectum; and at low levels in many other tissues. The mdr1 gene is also expressed in several human tumors, including many but not all tumors derived from the adrenal gland and the colon. In addition, increased expression was detected in a few tumors at the time of relapse following initial chemotherapy. Although controlled clinical studies will be required, our results suggest that measurement of mdr1 RNA may prove to be a valuable tool in the design of chemotherapy protocols.

https://www.pnas.org/content/pnas/84/1/265.full.pdf

Expression of a multidrug-resistance gene in human tumors and tissues

Spin trapping: ESR parameters of spin adducts.

Chemotherapy has proven to be an effective treatment for the cure and palliation of some human cancers (Chabner, 1982). Some tumors, however, appear to be intrinsically resistant to chemotherapy. For cancers that can be treated with chemotherapy, based on the hypothesis that resistance to single agents occurs with high frequency, protocols involving multiple drugs with different intracellular targets have been designed. In many cases, such as acute lymphocytic leukemia and neuroblastoma (Simone et al., 1982), Hodgkin’s disease (De-Vita and Hellman, 1982), and germ cell cancers (Paulson et al., 1982), dramatic results have been achieved with such protocols. However, all too frequently relapse occurs after such therapy and the recurrent tumors are resistant to further chemotherapy. In effect, such tumors develop a multidrug resistance (MDR) phenotype that is very similar to the intrinsic resistance of some primary cancers.

Expression of Multidrug Resistance Gene in Human Cancers

Asbestos fibers are human carcinogens with undefined mechanisms of action. In studies here, we examined signal transduction events induced by asbestos in target cells of mesothelioma and potential cell surface origins for these cascades. Asbestos fibers, but not their nonfibrous analogues, induced protracted phosphorylation of the mitogen-activated protein (MAP) kinases and extracellular signal-regulated kinases (ERK) 1 and 2, and increased kinase activity of ERK2. ERK1 and ERK2 phosphorylation and activity were initiated by addition of exogenous epidermal growth factor (EGF) and transforming growth factor-alpha, but not by isoforms of platelet-derived growth factor or insulin-like growth factor-1 in mesothelial cells. MAP kinase activation by asbestos was attenuated by suramin, which inhibits growth factor receptor interactions, or tyrphostin AG 1478, a specific inhibitor of EGF receptor tyrosine kinase activity (IC50 = 3 nM). Moreover, asbestos caused autophosphorylation of the EGF receptor, an event triggering the ERK cascade. These studies are the first to establish that a MAP kinase signal transduction pathway is initiated after phosphorylation of a peptide growth factor receptor following exposure to asbestos fibers.

https://cancerres.aacrjournals.org/content/canres/56/23/5334.full.pdf

Asbestos Causes Stimulation of the Extracellular Signal-regulated Kinase 1 Mitogen-activated Protein Kinase Cascade after Phosphorylation of the Epidermal Growth Factor Receptor

The role of membranes in the mechanism of action of the antineoplastic agent adriamycin. Spin-labeling studies with chronically hypoxic and drug-resistant tumor cells

Thomas R. Tritton

Papers

Asbestos Causes Stimulation of the Extracellular Signal-regulated Kinase 1 Mitogen-activated Protein Kinase Cascade after Phosphorylation of the Epidermal Growth Factor Receptor

The role of membranes in the mechanism of action of the antineoplastic agent adriamycin. Spin-labeling studies with chronically hypoxic and drug-resistant tumor cells

Adriamycin: a proposal on the specificity of drug action.

Adriamycin-induced changes in the surface membrane of sarcoma 180 ascites cells

Cellular transport of anthracyclines by passive diffusion. Implications for drug resistance.