Current Medicinal Chemistry - Volume 17, Issue 29, 2010

Cytokines are a large and growing family of hormone-like proteins that play a variety of roles in different physiological and pathological circumstances such as inflammation and immunity. Given their ability of influencing a number of biological phenomena such as cell growth, apoptosis, migration, angiogenesis and immune surveillance, cytokines play a key role also in cancer development and progression. Cytokine-based anticancer biotherapy represented one of the first types of anticancer approaches by exploiting either the direct antitumor effects of these proteins, or their immunostimulating properties, or their synergistic effects with conventional chemotherapeutics and other anticancer agents. Cytokine-based biotherapy is currently utilized for the routine treatment of different tumors in the clinical setting. However, due to their pleiotropic biological activities, administration of cytokines is often accompanied by significant side effects, which tempers the enthusiasm for the promising tumor response rates that can be observed in patients who are given this type of treatment. Advances in our understanding of the role of cytokines in modulating the tumor-host interactions as well as the improvement in patient selection are paving the way for a significant improvement of the therapeutic index (the ratio between efficacy and toxicity) of cytokines used as anticancer agents. This issue is an authoritative, comprehensive and critical overview on the biological rational, the preclinical and clinical findings as well as the potential developments of the use of cytokines (alone or in combination with other therapeutic agents) to fight cancer. In particular, Sandro Pasquali et al. provide an in depth coverage of the molecular and cellular mechanisms underlying the anticancer effects of interferon (IFN) alpha, one of the most studied cytokines in the oncology field; the Authors also report on the results of the utilization of this molecule in the clinical setting, with a focus on cutaneous melanoma. Tumor necrosis factor (TNF) is the focus of the essay by Loris Bertazza et al.: these Authors outline the controversies regarding the role of this cytokine in tumor biology; they also overview the clinical findings so far reported regarding the use of TNF as an anticancer agent and conclude with an original hypothesis to explain the apparently conflicting data surrounding the relationship between TNF and cancer. Arkadiusz Dudek et al. report on the anticancer properties of interleukin-2 (IL-2), one of the cytokines most prescribed in the oncology field. With introduction of novel kinase inhibitors, immunomodulatory molecules, cytokines, and vaccines for treatment of cancer there is an increased interest in combining these therapeutic strategies with IL-2: accordingly, the Authors discuss toxicity and established activity of IL-2 in the management of advanced malignancies, and speculate on future use of this cytokine for treatment of cancer. The emerging role of TNF-related apoptosis inducing ligand (TRAIL) in the development of effective anticancer strategies is highlighted by Shulin Wang: besides reviewing the molecular biology of this cytokine, the Author summarizes the results so far obtained and the hurdles encountered by using TRAIL in the fight against malignancies. More recently, two other cytokines have drawn the attention of researchers involved in the fight against cancer: interleukin- 18 (IL-18) and interleukin-24 (IL-24). The preclinical data so far available in favor but also against the use of these molecules in the treatment of cancer are the focus of the essays by Michael Robertson and Stephanie Kreis, respectively.

Cancer immunotherapy with interleukin-2 (IL-2) has demonstrated long term disease control in metastatic renal cell carcinoma and malignant melanoma. With introduction of novel kinase inhibitors, immunomodulatory molecules, cytokines, and vaccines for treatment of cancer there is an increased interest in combining these therapeutic strategies with IL-2. Here we discuss toxicity and established activity of IL-2 in the management of advanced malignancies, and speculate on future use of this cytokine for treatment of cancer.

The prominent role of interleukin (IL)-12 in inflammatory responses, especially in TH1 T cell differentiation, is well established. Moreover, in murine models of tumorigenesis, IL-12 displays remarkable antitumor properties that are mainly mediated by interferon (IFN)-γ secretion by CD4+, CD8+ T cells, natural killer (NK) or NK-T cells. Importantly, IL-12 through IFN-γ-dependent induction of the antiangiogenic factors interferon-inducible protein (IP) 10 and monokine induced by gamma interferon (MIG) contributes to tumor eradication. Recently, the structurally similar but functionally different cytokines IL-23 and IL-27 were discovered and related to the IL-12 family of cytokines. Each of those cytokines has its own specific effects on tumor growth. Similarly to IL12p70, antitumor effects of IL-27 are mediated via the IFNγ- IP10/MIG-axis and tumor-specific increase of cytotoxic T-lymphocyte activity. Additionally, IL-27 itself may mimic the function of IFN-γ due to the similarity in usage of JAK/STAT signalling molecules such as STAT1. The role of IL-23 in tumor growth to date is controversial. Whether IL-23 acts pro- or anticancerogenic seems to depend on a critical balance of STAT3 signalling in both the tumor and the immune cellular microenvironment of the tumor. At least for solid tumors the promising results from preclinical studies of systemic and on-site IL-12-based therapy did not prevail in clinical studies. In future combinatorial approaches using IL-12 together with other cytokines or antiangiogenic molecules have to be evaluated. This review focuses on anticancer effects of the IL-12 family in preclinical and clinical studies with an emphasis on colorectal cancer.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anticancer agent that selectively triggers apoptosis in various cancer cells by interacting with its proapoptotic receptors DR4 and KILLER/DR5. The intensive studies of TRAIL signaling pathways over the past decade have provided clues for understanding the molecular mechanisms of TRAIL-induced apoptosis in carcinogenesis and identified an array of therapeutic responses elicited by TRAIL and its receptor agonists. Preclinical and clinical studies have shown that recombinant TRAIL and the agonistic mono-antibodies targeting TRAIL receptors exhibit potent tumoricidal activities as monotherapies and that the combinatorial therapies of these agents in conjunction with other anticancer modalities such as chemo or radiotherapy amplify the activities of anticancer agents and widen the therapeutic window by overcoming tumor resistance to apoptosis and driving cancer cells to self-destruction. The identification of a number of biomarkers that predict tumor sensitivity of patients to TRAIL-based therapy shed a new light on the personalized therapeutic strategies targeting the TRAIL/TRAIL receptor pathway.

IL-24, previously known as melanoma differentiation antigen 7 (mda-7), is a member of the IL-10 family of cytokines and is mainly produced by Th2 cells and activated monocytes. Binding of IL-24 to either of its two heterodimeric receptors IL-20R1/IL-20R2 and IL-22R/IL-20R2 triggers phosphorylation and consequently activation of STAT3 and/or STAT1 in target tissues such as lung, testis, ovary, keratinocytes and skin. There is accumulating evidence that skin represents a major target tissue for IL-24 and related cytokines such as IL-19, -20, and -22. To date, the physiological properties of IL-24 are incompletely understood but available data indicate that it affects epidermal functions by increasing proliferation of dermal cells, suggestive of a possible role in psoriasis. However, the initial interest in IL-24 did not arise from its physiological signaling properties through its cognate receptors but rather because this cytokine has been reported to efficiently kill cancer cells independent of receptor expression and Jak-STAT signaling. These potentially intriguing properties have led to the development of adenovirally expressed IL-24, which was reported to induce selective cancer cell death in many different malignancies by activation or deactivation of a continuously growing list of distinct signaling pathways without harming surrounding healthy cells. In the present review we critically revisit and discuss the potential of IL-24 to become a selective and cancer cell-specific oncolytic drug and put these tentative properties into context with recent data on the physiological properties of this cytokine.

Alpha interferons (IFN) are type I IFNs that have pleiotropic effects on cell functions. A wealth of evidence exists that these cytokines exhibit a variety of biological effects different from those on viral replication, including antitumor activity. IFNs-alpha represent the cytokines exhibiting the longest record of use in clinical oncology for the treatment of over a dozen of cancer types, including some hematological malignancies and solid tumors. Although targeted anticancer agents have recently replaced IFN-alpha in the treatment of certain hematological (e.g. chronic myeloid leukemia) and solid (e.g. renal cell carcinoma) malignancies, this cytokine is still used for the treatment of patients with specific tumor types, such as cutaneous melanoma. Despite the intense work in preclinical tumor models and considerable experience in the clinical use of IFN-alpha, the mechanisms of action underlying tumor response is still a matter of open debate. In this review we describe the evidence supporting the main mechanisms underlying IFN-alpha anticancer effects using both preclinical and clinical findings; moreover, we focus on the results of IFN-alpha for the treatment of patients with high-risk cutaneous melanoma, one of the malignancies most resistant to conventional chemotherapy.

Tumor necrosis factor (TNF) is a cytokine with well known anticancer properties and is being utilized as anticancer agent for the treatment of patients with locally advanced solid tumors. However, TNF role in cancer biology is debated. In fact, in spite of the wealth of evidence supporting its antitumor activity, the cascade of molecular events underlying TNF-mediated tumor regression observed in vivo is still incompletely elucidated. Furthermore, some preclinical findings suggest that TNF may even promote cancer development and progression. With this work we intend to summarize the molecular biology of TNF (with particular regard to its tumor-related activities) and review the experimental and clinical evidence currently available describing the complex and sometime apparently conflicting relationship between this cytokine, cancer biology and antitumor therapy. We also propose a model to explain the dual effect of TNF based on the exposure time and cytokine levels reached within the tumor microenvironment. Finally, we overview recent research findings that might lead to new ways for exploiting the anticancer potential of TNF in the clinical setting.

Interleukin-18 (IL-18) is an immunostimulatory cytokine belonging to the IL-1 family. IL-18 can regulate both innate and adaptive immune responses through its effects on natural killer (NK) cells, monocytes, dendritic cells, T cells, and B cells. IL-18 acts synergistically with other pro-inflammatory cytokines to promote interferon-γ (IFN-γ) production by NK cells, T cells, and possibly other cell types. Systemic administration of IL-18 has been shown to have significant antitumor activity in several preclinical animal models. Phase I clinical trials of recombinant human IL-18 have demonstrated that it can be safely administered to patients with advanced cancer. Biologic effects of IL-18 therapy include activation of monocytes, NK cells, and T cells and production of IFN-γ as well as other cytokines in vivo. A phase II study of IL-18 in patients with metastatic melanoma confirmed its safety but suggested limited efficacy of IL-18 monotherapy in this setting. IL-18 appears to act predominantly as a costimulatory cytokine and its optimal use for cancer immunotherapy may be in combination with other immunostimulatory cytokines, vaccines, or monoclonal antibodies.

Different intervention trials have been so far conducted and others are ongoing to evaluate the effect of increased intake of n-3 polyunsaturated fatty acids (PUFAs) in the prevention of several disorders affecting lungs and airways. They have been focused on chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, alteration of lung function in cystic fibrosis, as well as asthma and cachexia in lung cancer patients. Their outcomes are not always consistent, but, if beneficial effects were observed, they have been related mainly to the anti-inflammatory action of n-3 PUFAs. On the contrary, trials investigating their effects on the development and progression of lung cancer are still not available. This in spite of the huge number of equivalent studies performed on other kind of cancers (breast, colon and prostate cancer), which share with lung cancer the highest incidence in Western countries and an elevated sensitivity to chemoprevention. Contrasting results were also obtained by the few epidemiological studies available on lung cancer. However, different experimental studies, performed in vivo and in vitro, provided strong indications of the anti-tumor action of n-3 PUFAs against lung cancer, and identified molecular mechanisms for their action. In this review our effort will concentrate in critically reviewing the current evidence for the beneficial effect of n-3 PUFAs in inflammatory and neoplastic disorders of lungs and airways, and in identifying possible molecular mechanisms underlying their effects.

Hepatitis B virus (HBV) infected hepatitis is the common infectious disease. In the World Conservative Estimate Plan, the number of persons chronically infected with HBV is more than 300 million. Current regimen of treatment is far from satisfactory, as it is associated with certain side effects and viral resistance capacity. Therefore, a serious attention has recently been paid to the design and development of new potent anti-HBV agents. A variety of drugs have been synthesized and screened for their anti-HBV effects. These include nucleosides, natural compounds, quinolines, benzodiazepines, indoles, etc. Many of them are in wide trend in current treatment regimen. In this review, we have presented the recent development on the design and development of all categories of HBV inhibitors studied.

In recent years, the number of useful chemical biology information of protein-protein interactions in the HIV life cycle and related inhibitors, is growing rapidly, which makes protein-protein interactions a new investigative area for antiviral drug intervention. This review will summarize recent work in this field, mainly focusing on the utilization of small molecules targeted against a variety of protein-protein interactions that have great therapeutic feasibility for HIV infection, and lastly outline some other important protein-protein interactions with a potential to advance into novel anti- HIV drug targets in future.

In the last decades, the treatment of obsessive-compulsive disorder (OCD) has been revolutioned by the introduction into the clinical practice of the selective serotonin (5-HT) reuptake inhibitors (SSRIs), following the observation of the unique response of OCD patients to clomipramine. However, if with no doubt the 5-HT system is central to the pharmacological treatment of OCD, it is unlikely that it represents the whole story. In fact, different studies suggest abnormalities of other neurotransmitters, neuropeptides or second messengers, so that it can be hypothesized that the possible heterogeneity of pathophysiological mechanisms might underlie the different clinical pictures and responses to treatment. Moreover, latest developments in the pharmacology of SSRIs have shown that they share the common property of 5-HT reuptake blockade, but, with the exception of citalopram and escitalopram, they do interact with other receptors and systems. In this paper, the latest findings on pharmacological treatments of OCD will be reviewed, together with a focus on putative targets for future drugs, such as the glutamate system or second messengers, and the problems related to treating OCD in different ages.

We have designed a number of 2-hydroxy (alkoxy)-2-aryl-4-alkyl-(5,6-alkyl)-morpholines with interesting biological activities, i.e. sympathomimetic, analgesic, drug metabolizing enzyme modulating ability, antioxidant potential, anti-inflammatory and anti-dyslipidemic properties. They are synthesised by reaction of the proper 2-aminoethanol with aryl-bromomethyl-ketone. The intermediate hydroxyaminoketone is spontaneously cyclised to form the tetrahydro-1,4-oxazine ring. The produced 2-hydroxy substituted morpholines form the 2-alkoxy derivatives. The 2-hydroxy or 2-alkoxy-1,4-oxazine derivatives can lose water or alcohol, to give styrene-type products. The conditions for oxazine ring formation and water or alcohol abstraction are investigated. Ionisation constants and partition coefficients have been determined and related to structure and activity. The biological activities of these compounds are quite interesting: The 2-phenyl analogues acquire the structural requirements for sympathomimetic amines, and present a structure related to the pethidine-type analgesics. Indeed, they show central dopaminergic and analgesic, antagonized by naloxone, activities. They also affect drug metabolising enzymes. The 2- phenyl and especially the 2-biphenyl derivatives are good antioxidants, also possessing anti-inflammatory and immunomodulating action. The later class of compounds reduces remarkably plasma triglycerides, total cholesterol and LDL-cholesterol in hyperlipidemic rats. Since NO plays a multiple role in atheromatosis and inflammation, some 2- nitroxy-alkoxy derivatives are synthesized and their NO-liberating ability assessed. These nitric esters are also found to be potent hypolipidemic-hypocholesterolemic agents. In a mechanism elucidation attempt, it is indicated that these derivatives may act as squalene synthase inhibitors.

Aneuploidy in the conceptus or fetus, occurs in 5-10% of all pregnancies and is a common reproductive problem in humans. Most aneuploid conceptuses die in utero, resulting in early pregnancy loss. Causes of recurrent miscarriage may include abnormal chromosomes in either partner, particularly translocations, antiphospholipid antibodies and uterine anomalies. Chromosomal aberrations in parents are a major pre-disposing factor and causative of abortion if carried over to the embryo. The transmission rate in the embryo can be speculated to be about 50%. Embryo morphology, developmental rates, and maternal age are correlated with chromosomal abnormalities. Translocation in either partner is one of the most important causes of recurrent miscarriage and the prognosis of subsequent pregnancy in couples with abnormal embryonic karyotype is poorer than that in couples with normal chromosome karyotypes. As for parents whose karyotypes are normal, the frequency of normal embryonic karyotypes significantly increases with the number of previous abortions and a normal karyotype in a previous pregnancy is a predictor of subsequent miscarriage. Recently, many kinds of genetic polymorphisms have also been found to be associated with recurrent miscarriages. In contrast, preimplantation genetic diagnosis for aneuploidy screening is sometimes performed in patients with unexplained recurrent miscarriages. We review genetic factors as a cause of miscarriage.

G-quadruplex stabilizing compounds have recently received increased interest due to their potential application as anticancer therapeutics. A significant number of structurally diverse G-quadruplex ligands have been developed. Some of the most potent and selective ligands currently known are macrocyclic structures which have been modeled after the natural product telomestatin or from porphyrin-based ligands discovered in the late 1990s. These two structural classes of G-quadruplex ligands are reviewed here with special attention to selectivity and structure-activity relationships, and with focus on the recent developments.