In order to respond to physiologic and pathologic states, GCs affect nearly every cell of the body and modulate the expression of approximately ten percent of the body’s genes. Actions of particular relevance to this chapter will be divided into effects on general cellular function, inflammation, systemic function, and nervous system function.

General cellular effects of GCs include the promotion of apoptosis and necrosis, which occur through the genomic mechanisms of gene trans-activation and trans-repression by the GR [10, 11]. The apoptotic effect of GCs is cell-type-specific, as well as time- and concentration-dependent [12]. However, the specific mechanisms of GC-induced apoptosis, their target genes, and their respective proteins remain incompletely understood [13–20]. An example of one such protein is NF-kB, whose DNA-independent repression induces apoptosis in many hematologic cell lines [15].

Anti-inflammatory effects of GCs include both the prevention and suppression of the inflammatory response. Specific actions depend on the type and dose of GCs used, the type and location of inflammation, and the type and number of immune cells involved. Anti-inflammatory actions of GCs occur via several mechanisms, including direct and indirect genomic repression. One example of such a mechanism includes the indirect repression of several mediators occurs via inhibition of transcriptional factor NF-kB. Collectively, these mechanisms minimize the proliferation, recruitment, and functional activity of lymphocytes, neutrophils, macrophage, and monocytes by blocking the expression of endothelial and intercellular adhesion molecules, decreasing prostaglandin-mediated cell adhesion, decreasing chemokine binding to leukocytes, and inhibiting plasminogen activator synthesis [21–24]. These mechanisms also minimize the functions of pro-inflammatory mediators such as chemokines, cytokines, adhesion molecules, arachidonic acid metabolites, platelet-activating factor release, and pro-inflammatory enzymes and peptides [25]. The above mechanisms have been preferentially exploited for use in various hematologic and solid malignancies.

Systemic effects of GCs cannot be fully addressed in this chapter; however, those particularly relevant to the treatment and complications of cancer therapy will be addressed in subsequent sections and are listed in Table 19.1. GCs have a multitude of effects on a wide range of organ systems including the vascular, gastrointestinal, hematologic, dermatologic, and metabolic systems. Specific examples of these effects include regulation of blood pressure via the alteration of tissue sensitivity to catecholamine and the aldosterone-like effect on fluid retention, alterations in the number of circulating red blood cells and neutrophils, promotion of protein catabolism, gluconeogenesis, and glycogen synthesis, as well as alteration of lipid and bone metabolism. GCs also regulate protective prostaglandins and cellular integrity in the GI tract and can result in the thinning of epithelial and connective tissue throughout the body, thereby affecting skin integrity.

Nervous system effects of GCs involve both the central nervous system (CNS) and peripheral nervous system (PNS) levels. Mechanistically, acute exposure to GCs results in neuronal hyper-polarization, which is the result of alterations in intracellular calcium levels, interactions with GC protein-coupled receptors, and induction of MAP kinase cascades. Chronic exposure results in decreased quantity of neurons, induction of apoptotic cell death, impaired regenerative properties, and decreased neuronal survival [26]. Clinically, GC exposure impacts cognition (memory, mood, and personality), sleep patterns, pain perception, body temperature, muscle strength, and vasogenic edema.

Mechanisms of GC resistance remain poorly understood and vary with the genetic background of the patient, steroid type, disease type, and treatment regimen.

One mechanism of GC resistance involves apoptosis , which, amazingly, can produce seemingly dichotomous results. Such dichotomies are epitomized by the paradoxical effects that GCs have across various malignancies, as well as in response to various chemotherapy agents. One such example includes the pro-apoptotic effect of GCs on hematopoietic malignancies (discussed in the Mechanism of Action section), in contrast to the anti-apoptotic effects of GCs on many solid malignancies. For example, Zhang et al. [27] demonstrated dexamethasone and other GCs cause resistance to several cytotoxic chemotherapies and radiation in xenografted prostate cancer cells. A second mechanism of GC resistance involves inhibiting apoptosis-inducing receptors, signaling molecules, caspase enzymes, and mitochondrial membrane stabilizing proteins [28]. For example, dexamethasone has been shown to antagonize both mitochondrial and death receptor apoptotic pathways across various cancer cell lines [28], thus resulting in dexamethasone-induced apoptotic resistance in cell lines of solid malignancies, such as melanoma, neuroblastoma, gliomas, adenocarcinomas (e.g., breast), carcinomas (e.g., cervical), and bone cancers. Interestingly, many of the apoptosis genes repressed by GCs in carcinoma cell lines are the very same genes induced by GCs in hematopoietic malignancy cell lines [28, 29]. These seemingly paradoxical effects have been postulated and include cell-type specific differences in both transcriptional regulation and cell cycle progression, as well as cell-type differences in the development of mutations of GC function [28, 30–34]. A third mechanism of resistance involves perturbations of the GR gene and the GR receptor [32, 35–41]. A fourth mechanism of resistance involves activities essential to epithelial cell survival, including alterations of intercellular communication and extracellular matrix attachment, which have resulted in the chemotherapy resistance of many solid malignancies [42].

A fifth mechanism of resistance involves iatrogenic factors. For example, chronic exposure to GCs reduces both GR expression and GR protein stability [43–46]. In another example, concomitant use of medications that interact with the cytochrome P450 system can reduce the efficacy of GC metabolism and bioavailability [47–49]. In a third example, states of chronic inflammation can reduce the efficacy of GCs through the activation of both GR-dependent and GR-independent signaling pathways. Chronic inflammation can be induced by: (1) cigarette smoking, which induces an oxidative stress that affects both GR nuclear translocation and nuclear cofactors (2) inflammatory conditions such as asthma, which promote immune-mediated cytokines such as IL2 and IL-4, which diminish GR translocation and binding affinity at target cells, (3) viral infections, which reduce both GR nuclear translocation and GC functions, (4) allergen exposures, which affect both GR function and GR-binding affinity, (5) changes in the cellular micro-environment, such as during disease progression, which alter GR translocation and P-glycoprotein-mediated cellular ligand accumulation, (6) oxidative stress, which attenuates histone deacetylase-2 (HDAC2) activity and expression, thereby limiting recruitment of GC to sites of action in the genome by GR, and (7) hypoxia, which induces cellular dysfunction and impairs GR trans-activation [32].

In general, GC side effects are common, correlated to dose and duration. For example, in a chart review of 88 patients with brain metastases, Sturdza et al. [97] reported that 91% of the patients receiving 16 mg or more daily and 65% of the patients receiving less than 16 mg daily experienced at least one side effect (p = 0.006). Hypoalbuminemia exacerbates GC side effects because such a state results in an increased percentage of unbound steroid [102].