Current Drug Targets (v.17, #2)

Meet Our Editorial Board Member: by Subhash C. Basu (137-137).

Targeting the Ataxia Telangiectasia Mutated Protein in Cancer Therapy by Donatella Vecchio, Guido Frosina (139-153).
Genotoxic anticancer drugs explicate their effects damaging DNA, thus triggering a coordinated signal-transduction network called DNA Damage Response (DDR). Ataxia Telangiectasia Mutated (ATM) protein plays a central role in this response: activated by DNA damage, ATM phosphorylates itself and downstream effectors that arrest cell cycle allowing for DNA repair or, should DNA damage be too severe and not retrievable, inducing apoptosis. ATM is a worth-investigating target for tumor radio- and chemosensitization. During last years, pharmaceutical industries and research laboratories have developed a series of small molecules, capable to inhibit ATM with increasing specificity. Several preclinical studies have demonstrated that these inhibitors alone or in association with other treatments may improve therapeutic outcomes. In this review we discuss ATM inhibitors so far developed, focussing on recent acquisitions on their potential antineoplastic usefulness.

The Role of JNK Signalling in Responses to Oxidative DNA Damage by Zeeshan Shaukat, Dawei Liu, Rashid Hussain, Mahwish Khan, Stephen L. Gregory (154-163).
The production of reactive oxygen species is a normal part of cell physiology, but many internal and external stimuli are able to trigger the production of excess levels of oxidants that are potentially damaging. The threat of oxidative damage is particularly significant to DNA, as damaged bases can interfere with replication to generate lasting mutations. Signalling through the JNK pathway is a key cellular response to oxidative damage. Depending on the intensity and duration of the damage signal, JNK signalling can lead to distinct alternative responses including DNA repair, anti-oxidant production or cell death. These responses are highly relevant to cancer therapy, as tumours are often under oxidative stress that produces elevated JNK levels and therapy often involves inducing DNA damage with the intention of driving cell death. In this review we examine the causes and consequences of JNK activation that relate to oxidative DNA damage, with a focus on the potential therapeutic implications.

Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance by Gabriela Nestal de Moraes, Laura Bella, Stefania Zona, Matthew J. Burton, Eric W.-F. Lam (164-177).
FOXO3a and FOXM1 are two forkhead transcription factors with antagonistic roles in cancer and DNA damage response. FOXO3a functions like a typical tumour suppressor, whereas FOXM1 is a potent oncogene aberrantly overexpressed in genotoxic resistant cancers. FOXO3a not only represses FOXM1 expression but also its transcriptional output. Recent research has provided novel insights into a central role for FOXO3a and FOXM1 in DNA damage response. The FOXO3a-FOXM1 axis plays a pivotal role in DNA damage repair and the accompanied cellular response through regulating the expression of genes essential for DNA damage sensing, mediating, signalling and repair as well as for senescence, cell cycle and cell death control. In this manner, the FOXO3a-FOXM1 axis also holds the key to cell fate decision in response to genotoxic therapeutic agents and controls the equilibrium between DNA repair and cell termination by cell death or senescence. As a consequence, inhibition of FOXM1 or reactivation of FOXO3a in cancer cells could enhance the efficacy of DNA damaging cancer therapies by decreasing the rate of DNA repair and cell survival while increasing senescence and cell death. Conceptually, targeting FOXO3a and FOXM1 may represent a promising molecular therapeutic option for improving the efficacy and selectivity of DNA damage agents, particularly in genotoxic agent resistant cancer. In addition, FOXO3a, FOXM1 and their downstream transcriptional targets may also be reliable diagnostic biomarkers for predicting outcome, for selecting therapeutic options, and for monitoring treatments in DNA-damaging agent therapy.

Renin-Angiotensin-Aldosterone System (RAAS) is well established in renovascular and cardiovascular functions. The modulators of this system are significantly used for regulating elevated blood pressure in human and animals. Recently, it has also been documented to produce neurological actions. The abnormalities of this system raise renin, angiotensin (AT), angiotensin converting enzyme (ACE) activity, and aldosterone in circulation and nerve tissues. In the nervous system, abundant rise of these components cause neuronal damage and neurodegeneration. ACE contributes to degradation of β-amyloid in the brain, that is responsible for Alzheimer disease (AD). But, angiotensin converting enzyme-2 (ACE-2) mediated release of angiotensin1-7 (AT1-7) peptide in nerve tissue has potential neuroprotective actions. This review focuses on the current perspectives of the RAAS in neurodegeneration along with possible cellular and molecular mechanisms. Also, we have discussed the current evidence of RAAS modulators in the management of neuropathic pain in human and animals. Thus, we believe that, in the future, RAAS modulators may play a great role in the management of neuropathic pain and other neurodegenerative disorders such as AD, Parkinson disease (PD) and amyotrophic lateral sclerosis. But, more extensive clinical research is required for utilizing RAAS modulators in neurodegenerative disorders.

The androgen receptor (AR) is a ligand-inducible transcription factor that regulates target gene expression. Androgen signaling has been considered a putative explanation for gender differences in urothelial carcinoma (UC) incidence. In the absence of established risk factors, men still experience a threefold risk of UC as compared to women. Multiple investigations to modulate the AR have been performed with in vitro and in vivo models of UC. Down-regulation of the AR has been shown to inhibit UC growth through increased apoptosis, decreased cell proliferation, and decreased cell migration. AR activation up-regulates EGFR and HER2/neu expression contributing to UC progression. UC is more easily induced in male than female models and the incidence of chemically-induced UC is decreased by castration and the addition of estrogens; it is increased by testosterone. Epithelial to mesenchymal transition (EMT) has been postulated to be androgen-driven in UC and affects chemotherapy sensitivity. UC has not achieved the same therapeutic advances that have been seen in other tumor types in recent years. Androgen-driven events may account for some of the treatment resistance seen in this tumor type. Novel agents which disrupt androgen synthesis and/or AR signaling are in development and some (abiraterone, enzalutamide) are approved for advanced prostate cancer. Biomarker AR-driven clinical trials of highly effective anti-androgen therapy (HEAT) agents in UC present a promising picture.

Nanocarriers Based Anticancer Drugs: Current Scenario and Future Perceptions by Rakesh Raj, Pooja Mongia, Suresh Kumar Sahu, Alpana Ram (206-228).
Anticancer therapies mostly depend on the ability of the bioactives to reach their designated cellular and subcellular target sites, while minimizing accumulation and side effects at non specific sites. The development of nanotechnology based drug delivery systems that are able to modify the biodistribution, tissue uptake and pharmacokinetics of therapeutic agents is considered of great importance in biomedical research and treatment therapy. Controlled releases from nanocarriers can significantly enhance the therapeutic effect of a drug. Nanotechnology has the potential to revolutionize in cancer diagnosis and therapy. Targeted nano medicines either marketed or under development, are designed for the treatment of various types of cancer. Nanocarriers are able to reduce cytotoxic effect of the active anticancer drugs by increasing cancer cell targeting in comparison to conventional formulations. The newly developed nano devices such as quantum dots, liposomes, nanotubes, nanoparticles, micelles, gold nanoparticles, carbon nanotubes and solid lipid nanoparticles are the most promising applications for various cancer treatments. This review is focused on currently available information regarding pharmaceutical nanocarriers for cancer therapy and imaging.

The Use of Mesenchymal Stem Cells for the Treatment of Autoimmunity: From Animals Models to Human Disease by Alessandra Fierabracci, Andrea Del Fattore, Marta Muraca, Domenico Vittorio Delfino, Maurizio Muraca (229-238).
Mesenchymal stem cells are multipotent progenitors able to differentiate into osteoblasts, chondrocytes and adipocytes. These cells also exhibit remarkable immune regulatory properties, which stimulated both in vitro and in vivo experimental studies to unravel the underlying mechanisms as well as extensive clinical applications. Here, we describe the effects of MSCs on immune cells and their application in animal models as well as in clinical trials of autoimmune diseases. It should be pointed out that, while the number of clinical applications is increasing steadily, results should be interpreted with caution, in order to avoid rising false expectations. Major issues conditioning clinical application are the heterogeneity of MSCs and their unpredictable behavior following therapeutic administration. However, increasing knowledge on the interaction between exogenous cell and host tissue, as well as some encouraging clinical observations suggest that the therapeutic applications of MSCs will be further expanded on firmer grounds in the near future.

Alcohol is the main risk factor for death and disability. The treatment of alcohol dependence (AD) is a complex activity as the variables are numerous; however, those which must necessarily be taken into account are the type of AD, the internal comorbidities and the presence of any psychiatric comorbidity. Liver problems are one of the most common causes of alcohol-related liver damage. 45% of deaths from cirrhosis are alcohol-related. Thus, the treatment of AD must often deal with a more or less severe liver disease, which influences the choice of anticraving drug. As chronic liver disease is often present, and as in a substantial proportion of cases, because there is a correlation with viral infections or with hepatocellular carcinoma (HCC), it is clear that hepatologists should make use of nonhepatotoxic molecules. In cases of mild liver disease, all available drugs might be used, but we recommend caution because the liver is usually fragile due to the harmful abuse of alcohol. In the advanced liver disease, the choice of treatment is reduced. A psychosocial approach such as attending support groups could be the first choice. In cases of compensated cirrhosis with or without HCC, or in cases of HCC without cirrhosis, metadoxine, acamprosate and baclofen can be used. In decompensated forms the only drug tested to date has been baclofen. In alcohol-related liver disease a professional team with hepato-alcohologists is also necessary, especially for liver transplantation programs.