Molecular pathways: old drugs define new pathways: non-histone acetylation at the crossroads of the DNA damage response and autophagy

Histone deacetylases (HDAC) modulate acetylation and the function of histone and non-histone proteins. HDAC inhibitors have been developed to block the aberrant action of HDACs in cancer, and several are in clinical use (vorinostat, romidepsin, and valproic acid). Detailed understanding of their action is lacking, however, and their clinical activity is limited in most cases. Recently, HDACs have been involved in the control of the DNA damage response (DDR) at several levels and in directly regulating the acetylation of a number of DDR proteins (including CtIP and Exo1). Mechanistically, acetylation leads to the degradation of double-strand break repair enzymes through autophagy, providing a novel, direct link between DDR and autophagy. These observations, obtained in yeast cells, should now be translated to mammalian model systems and cancer cells to reveal whether this acetylation link is maintained in mammals, and if and how it is deregulated in cancer. In addition to HDACs, DDR and autophagy have been addressed pharmacologically, suggesting that the acetylation link, if involved in cancer, can be exploited for the design of new anticancer treatments.     

Metformin and cancer: new applications for an old drug

Metformin, one of most widely prescribed oral hypoglycemic agents, has recently received increased attention because of its potential antitumorigenic effects that are thought to be independent of its hypoglycemic effects. Several potential mechanisms have been suggested for the ability of metformin to suppress cancer growth in vitro and vivo: (1) activation of LKB1/AMPK pathway, (2) induction of cell cycle arrest and/or apoptosis, (3) inhibition of protein synthesis, (4) reduction in circulating insulin levels, (5) inhibition of the unfolded protein response (UPR), (6) activation of the immune system, and (7) eradication of cancer stem cells. There is also a growing number of evidence, mostly in the form of retrospective clinical studies that suggest that metformin may be associated with a decreased risk of developing cancer and with a better response to chemotherapy. There are currently several ongoing randomized clinical trials that incorporate metformin as an adjuvant to classic chemotherapy and aim to evaluate its potential benefits in this setting. This review highlights basic aspects of the molecular biology of metformin and summarizes new advances in basic science as well as intriguing results from recent clinical studies.     

The new generation of breast cancer clinical trials: the right drug for the right target

The principal mission of the Breast International Group (Big), Transbig, and the Breast European Adjuvant Study Team (Breast), all located at the Jules Bordet Institute in Brussels, is to accelerate and facilitate the initiation and conduct of large and difficult breast cancer clinical trials. This is made possible through the excellent network of research groups, scientists, physicians and many other collaborators deeply committed to academic clinical and translational research. A clear example of this collaboration is the HERA trial (Herceptin Adjuvant trastuzumab in HER2 positive early breast cancer) that contributed to a change of clinical practice and improved the prognosis for this particular patient population. In addition, there is an important new generation of adjuvant trials, for example, Mindact, which is evaluating the use of microarray technology in treatment decision making, and the Altto and Neo-Altto studies, which have just started and are evaluating lapatinib, a small tyrosine kinase molecule given either adjuvantly or neo-adjuvantly, alone, sequentially or in combination with trastuzumab, in patients with HER2 positive early breast cancer. The latter studies, with their strong translational research component, aim to determine which tumour profiles will best benefit from lapatinib as opposed to treatment with trastuzumab alone.     

Multi-targeted therapy of cancer by niclosamide: A new application for an old drug

The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified niclosamide as a potential anticancer agent by various high-throughput screening campaigns. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. A number of studies have established the anticancer activities of niclosamide in both in vitro and in vivo models. Moreover, the inhibitory effects of niclosamide on cancer stem cells provide further evidence for its consideration as a promising drug for cancer therapy. This article reviews various aspects of niclosamide as they relate to its efficacy against cancer and associated molecular mechanisms.     

MGBG: Teaching an old drug new tricks

Methylglyoxalbisguanylhydrazone or MGBG is an agent with a uniquemechanism of action (polyamine biosynthesis inhibition). MGBGwas discarded in the 1960s because of severe mucositis and othertoxicities. New clinical trials in the late 1970s and early1980s utilized weekly administration and indicated MGBG hadsignificant activity in patients with chemotherapy-refractoryHodgkin's and non-Hodgkin's lymphoma. In addition, some activitywas noted in patients with head and neck, prostate, esophageal,and endometrial cancer. The toxicities on the weekly schedulewere minimal and no myelosuppression was noted. Based on MGBG'sspectrum of antitumor activity and its activity in severelydebilitated patients, we hypothesize that MGBG may have greaterantitumor activity in patients who are malnourished (possiblybased on polyamine depletion). MGBG is a good candidate fortreatment of AIDS-associated NHL because it has proven activityin patients with NHL which is not associated with AIDS, crossesthe blood brain barrier, is non-myelosuppressive, and appearsto work in patients with inanition (no polyamines availableto reverse MGBG's antitumor effects). Clinical trials are ongoingto determine the activity of MGBG in AIDS-associated NHL andother diseases. Based on encouraging initial results, it appearsMGBG may become part of our therapeutic armamentarium. MGBG, polyamine, AIDS, Hodgkin's lymphoma, non-Hodgkin's lymphoma     

Cardiac toxicity: old and new issues in anti-cancer drugs

Although rare, cardiotoxicity is a significant complication of cancer treatment. The incidence and severity of cardiovascular side effects are dependent on the type of drugs used, dose and schedule employed, and age of patients, as well as the presence of coexisting cardiac diseases and previous mediastinal irradition. Classically, anthracyclines are among one of the most active agents in oncology, but their use is often hampered by their cumulative dose-limiting cardiotoxicity. In the past decade, combination therapy with new drugs such as taxanes of anti-EGFR, and Her-2 therapy as a single agent have also resulted in unexpected cardiotoxicity. Cardiac damage can be secondary to an alteration of cardiac rhythm, changes in blood pressure and ischaemia, and can also alter the ability of the heart to contract and/or relax. The clinical spectrum of these toxicities can range from subclinical abnormalities to being catastrophic, life-threatening and sometimes fatal. Knowledge of this toxicity can aid clinicians to choose the optimal and least toxic regimen suitable for an individual patient. In this work we present an exhaustive review of the cardiovascular side effects associated to new anticancer drugs, from new formulations of anthracyclines to tyrosine kinase inhibitors and monoclonal antibodies.     

Thalidomide: an old drug with new action

Thalidomide is a drug that, since its development, has made history in the world of medicine--having been withdrawn and now has returned with a boom as an anticancer and immunomodulatory drug. However, its mode of action in various diseases (i.e. different types of hematologic malignancies, solid tumors) as well as in various infections (i.e. pneumonia, tuberculosis, HIV infection etc.) and related inflammatory conditions is not well understood. As the immune system plays an important role in the pathogenesis of both infection-related as well as noninfectious (i.e. cancer) inflammatory diseases, much research has been done in the past few years to discover and design better immunomodulatory agents. Such immunomodulatory agents should be able to target the immune system in such a way that host suffers minimum damage and normal function of the immune system remains intact. In the present review an attempt is made to highlight the immunomodulatory action of thalidomide in various pathologic conditions.     

Novel cytotoxic drugs: old challenges, new solutions

The discovery of cytotoxic agents was revolutionary for anticancer therapy in the last century, improving survival rates and the quality of life of patients with different types of tumours. However, the development of agents that combine efficacy, safety and convenience remains a great challenge, due to the narrow therapeutic index of some drugs, the fact that they may damage not only cancer cells, but also normal and healthy tissue and the occurrence of resistance, limiting anticancer efficacy. Novel cytotoxic agents have brought certain advantages over the conventional ones, such as shorter administration time, mechanisms to overcome drug resistance and lower incidence of adverse events. In this review we highlight the development of promising novel cytotoxic drugs that will hopefully offer not only gains in efficacy, but also in safety, tolerability and convenience in the treatment of patients with cancer.     

Anti-inflammatory strategies and hemostatic agents: old drugs, new ideas

Hemostatic abnormalities occur following injury associated with both cardiac and noncardiac surgery. These changes are part of inflammatory pathways with signaling mechanisms that link these diverse pathways. The inflammatory response to surgery is exacerbated by allogeneic blood transfusion by enhancing intrinsic inflammatory activity and directly increasing plasma levels of inflammatory mediators. Surgical patients can be preventively treated with pharmacologic agents to modulate inflammatory responses. Multiple studies have reported preventive pharmacologic therapies to reduce bleeding and the need for allogeneic transfusions in surgery. Strategies for cardiac surgical patients during cardiopulmonary bypass include administration of either lysine analogs, such as epsilon aminocaproic acid and tranexamic acid, or the serine protease inhibitor aprotinin.     

Urothelial tumorigenesis: a tale of divergent pathways

Urothelial carcinoma of the bladder is unique among epithelial carcinomas in its divergent pathways of tumorigenesis. Low-grade papillary tumours rarely become muscle-invasive and they frequently harbour gene mutations that constitutively activate the receptor tyrosine kinase-Ras pathway. By contrast, most high-grade invasive tumours progress to life-threatening metastases and have defects in the p53 and the retinoblastoma protein pathways. Correcting pathway-specific defects represents an attractive strategy for the molecular therapy of urothelial carcinomas.