Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting

International mobility, sexual behaviour and HIV-related characteristics of men who have sex with men residing in Belgium

BACKGROUND: European men who have sex with men (MSM) continue to be disproportionally affected by the human immunodeficiency virus (HIV). Several factors are contributing to the rates of new HIV infections among MSM. The aim of this study was to investigate the potential role of travel behaviour and sexual mobility in the spread of HIV and sexually transmitted infections (STI) among European MSM. METHODS: Belgian data from the first pan-European MSM internet survey EMIS was used (n=3860) to explore individual and contextual determinants of sexual behaviour among MSM, who resided in Belgium at the time of data collection and who reported having had sexual contact abroad in the last 12 months. Descriptive and bivariate analyses were performed. Odds ratios and 95% confidence intervals were calculated by means of logistic regression. RESULTS: MSM who practiced unprotected anal intercourse UAI during their last sexual encounter abroad were less likely to be living in a large city (OR:0.62, 95% CI:0.45-0,86, p<0.01) and more likely to be HIV positive (OR:6.20, 95% CI:4.23-9.06, p<0.001) ), to have tested HIV positive in the last 12 months (OR:3.07, 95% CI:1.07-8.80, p<0.05), to have been diagnosed with any STI in the last 12 months (OR:2.55; 95% CI:1.77-3.67, p<0.05), to have used party drugs (OR:2.22, 95% CI:1.59-3.09, p<0.001), poppers (OR:1.52, 95% CI:1.07-2.14, p<0.001) and erection enhancing substances (OR:2.23, 95% CI:1.61-3.09, p<0.001) compared to MSM who did not have UAI with their last sexual partner abroad. Men having had UAI in the last 12 months were more likely to have done so in a neighbouring country of Belgium (OR:1.66, 95% CI:1.21-2.29, p<0.001). Different sexual behavioural patterns related to condom use and drug use were identified according to HIV test status among travelling men. CONCLUSIONS: The results of this study provide evidence for the role of international mobility and sexual behavior while travelling, in the spread of HIV and STI among MSM in Europe. Further, the findings underline the need for development of European cross-border HIV and STI interventions with coherent messages and prevention policies for MSM

Caspases leave the beaten track: caspase-mediated activation of NF-κB

The proteolytic activity of the cysteinyl aspartate–specific proteases, named caspases, mainly connotes their central role in apoptosis and inflammation. In this review we report on recent data on the role of caspases in the activation of nuclear factor κB (NF-κB), a transcription factor that fulfils a central role in innate and adaptive immunity, in cellular stress responses and in the induction of anti-apoptotic factors. Two different mechanisms by which caspases activate the NF-κB pathway are discussed

Tumor necrosis factor-induced lethal hepatitis: pharmacological intervention with verapamil, tannic acid, picotamide and K76COOH.

AbstractTumor necrosis factor (TNF) induces hepatitis when injected in human beings or in rodents. The molecular mechanism by which TNF induces hepatic distress remains largely unknown, although induction of apoptosis of hepatocytes appears to be an essential step. In order to increase the therapeutic value of TNF, we have studied the protective activity of several molecules and found that four chemically totally different substances confer significant protection in the model of TNF-induced lethal hepatitis in mice sensitized with D-(+)-galactosamine (GalN), but not in mice sensitized with actinomycin-D (ActD) or against anti-Fas-induced lethal hepatitis. Verapamil, a calcium-channel blocker, tannic acid, picotamide, a thromboxane A2 receptor antagonist, and K76COOH, an inhibitor, amongst others, of complement, protected significantly against induction of lethality, release of the liver-specific enzyme alanine aminotransferase (ALT) and induction of apoptosis in the liver after TNF/GalN, except for K76COOH, which paradoxically increased ALT values after challenge, and which also protected against TNF/GalN in complement-deficient mice. The data suggest that activation of platelets and neutrophils, as well as induction of inflammation occur in the TNF/GalN model, but not in the TNF/ActD or anti-Fas models, in which direct induction of apoptosis of hepatocytes may be more relevant. The protective activity of the drugs may lead to an increase in therapeutic value of TNF

Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ

Corticosteroid-binding globulin (CBG), a negative acute phase protein produced primarily in the liver, is responsible for the transport of glucocorticoids (GCs). It also modulates the bioavailability of GCs, as only free or unbound steroids are biologically active. Fluctuations in CBG levels therefore can directly affect GC bioavailability. This study investigates the molecular mechanism whereby GCs inhibit the expression of CBG. GCs regulate gene expression via the glucocorticoid receptor (GR), which either directly binds to DNA or acts indirectly via tethering to other DNA-bound transcription factors. Although no GC-response elements (GRE) are present in the Cbg promoter, putative binding sites for C/EBPβ, able to tether to the GR, as well as HNF3α involved in GR signaling, are present. C/EBPβ, but not HNF3α, was identified as an important mediator of DEX-mediated inhibition of Cbg promoter activity by using specific deletion and mutant promoter reporter constructs of Cbg . Furthermore, knockdown of C/EBPβ protein expression reduced DEX-induced repression of CBG mRNA, confirming C/EBPβ’s involvement in GC-mediated CBG repression. Chromatin immunoprecipitation (ChIP) after DEX treatment indicated increased co-recruitment of C/EBPβ and GR to the Cbg promoter, while C/EBPβ knockdown prevented GR recruitment. Together, the results suggest that DEX repression of CBG involves tethering of the GR to C/EBPβ

Phytochemicals and Cancer Chemoprevention: Epigenetic Friends or Foe?

Cancer, as one of the non-communicable diseases, remains one of the leading causes of death around the world. Since immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and therapy sensitivity. Recent successes of therapeutic interventions in cancer and inflammatory diseases using epigenetic modifiers such as histone deacetylase inhibitors and inhibitors of DNA methylation suggest that epigenetic reprogramming plays an important role in the aetiology of these diseases. Epigenetic changes in DNA methylation patterns at CpG sites (epimutations) or corrupt chromatin states of tumor promoting genes and noncoding RNAs, recently emerged as major governing factors in tumor progression and cancer drug sensitivity. Epigenetic defects (epimutations) are thought to be more easily reversible (when compared with genetic defects) and, as such, have inspired efforts to identify novel compounds that correct epimutations or prevent disease progression. Given the fact that epigenetic modifications occur early in carcinogenesis and represent potentially initiating events in cancer development, they have been identified as promising new targets for chemoprevention strategies. Numerous clinical, epidemiological and laboratory studies have identified various promising nutritional anti-inflammatory compounds as chemopreventive agents, which affect carcinogenic epigenetic marks in the body and the host immune system, and protect against aggressive cancer malignancies. This has recently launched reexploration of chemopreventive phytochemicals for identification of epigenetic targets which allow epigenetic (re)programming of cancer stem cells, prevent metastasis or sensitize for drug sensitivity. This review will discuss mechanisms of epigenome plasticity by cancer-inflammation and chemopreventive phytochemicals

Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols

Background: Multidrug resistance (MDR) is a major obstacle in cancer treatment and is often the result of overexpression of the drug efflux protein, P-glycoprotein (P-gp), as a consequence of hyperactivation of NF-kappa B, AP1 and Nrf2 transcription factors. In addition to effluxing chemotherapeutic drugs, P-gp also plays a specific role in blocking caspase-dependent apoptotic pathways. One feature that cytotoxic treatments of cancer have in common is activation of the transcription factor NF-kappa B, which regulates inflammation, cell survival and P-gp expression and suppresses the apoptotic potential of chemotherapeutic agents. As such, NF-kappa B inhibitors may promote apoptosis in cancer cells and could be used to overcome resistance to chemotherapeutic agents. Results: Although the natural withanolide withaferin A and polyphenol quercetin, show comparable inhibition of NF-kappa B target genes (involved in inflammation, angiogenesis, cell cycle, metastasis, anti-apoptosis and multidrug resistance) in doxorubicin-sensitive K562 and -resistant K562/Adr cells, only withaferin A can overcome attenuated caspase activation and apoptosis in K562/Adr cells, whereas quercetin-dependent caspase activation and apoptosis is delayed only. Interestingly, although withaferin A and quercetin treatments both decrease intracellular protein levels of Bcl2, Bim and P-Bad, only withaferin A decreases protein levels of cytoskeletal tubulin, concomitantly with potent PARP cleavage, caspase 3 activation and apoptosis, at least in part via a direct thiol oxidation mechanism. Conclusions: This demonstrates that different classes of natural NF kappa B inhibitors can show different chemosensitizing effects in P-gp overexpressing cancer cells with impaired caspase activation and attenuated apoptosis