Current Pharmaceutical Design - Volume 13, Issue 33, 2007

The development of cancer therapies has diversified tremendously in the last decade and this development is in part due to our significantly improved understanding of the biological processes leading to tumor progression and metastasis. Despite this encouraging development, the success rate of cancer therapies is still disappointingly low. Investigating such treatment failures and shortcomings can greatly advance our understanding of tumor biology. For example, the study of drug resistant phenotypes in tumors has led to either the discovery of genes responsible for the phenotype and/or the identification of pathways that substitute or bypass those pathways targeted by the drugs. Such crucial findings guide researchers in the development of analogues of conventional drugs or result in the discovery of new anti-cancer reagents many of which are either contained within natural foods or are novel compounds isolated from plants or marine life. The current issue of Current Pharmaceutical Design reflects some of those most recent approaches in the development of anti-cancer drugs, that is the attempt to either identify and target specific signaling pathways used by tumor cells or to characterize novel anti-cancer agents. To reflecting these recent research efforts, this issue of “Anti-Cancer-Drugs” consists two parts: the first part contains two reports on novel approaches and novel molecular targets to either inhibit undesirable or to reconstitute proper signaling in cancer cells and thus an effort to revert cancer cells into a mortal somatic cell. To this end, Bianco et al. [1] describe efforts of combination therapies that bypass mechanisms, which render tumor cells resistant to blockers of epidermal growth factor (EGF)-receptor mediated signaling. Pennington et al. [2] outline strategies that target redox-sensitive signaling factors such as thioredoxin and thioredoxin reductase for cancer therapy. The idea here is to revert the pro-survival signals that tumor cells receive and thus promote the apoptosis induced by oxidative stress. This represents an attractive approach to render tumor cells susceptible to various otherwise only moderately effective treatments and drugs. The second part of this issue contains several reports on the discovery of novel anti-cancer agents that had originally been used for therapy of other diseases and disorders. Michaelis et al. [3] report on the efficacy of Valproic acid (VP) for treatment of various leukemias and solid tumors. Moreover, the authors review recent developments in the research surrounding VP and its anti-neoplastic activities. Nishino et al. [4] assess the effects of various phytochemicals on cancer growth as well as the potential molecular targets of such agents. Ichikawa et al. [5] review the re-discovery of ancient drugs as well as substances from fruits and plants, which had been used in ancient medicines. Their review focuses on the effect of such substances on targeting the NF-κB pathway and other signaling pathways known to be involved in tumorigenesis. Thomas Adrian [6] provides a comprehensive overview of novel marine-derived anti-cancer drugs, their origins as well as their efficacy in the treatment of various malignancies and - where known - their mode of action and molecular targets. Finally, Le Tourneau et al. [7] outline the difficulties and challenges involved in tumor therapy with one of those marine-derived anti-cancer agents, specifically Aplidine. I would like to thank all the authors for their efforts in reviewing their own research data and the encompassing body of literature in order to make this issue a comprehensive overview of current efforts to identify and target molecular pathways as well as to discover efficacious novel anti-cancer drugs.

The epidermal growth factor receptor (EGFR) has been widely used as a target for novel anticancer agents, such as blocking antibodies and small molecular weight tyrosine kinase compounds. In spite of recent advances in cancer cell biology, leading to the introduction of clinically active new drugs, such as cetuximab, panitumumab and erlotinib, unfortunately disease control remains unsuccessful due to the presence of constitutive resistance to EGFR inhibitors in most patients and the development of acquired resistance in the responders. A large number of molecular abnormalities in tumor cells seem to partly contribute to their resistance to anti-EGFR therapy: increased angiogenesis, constitutive activation of downstream mediators, overexpression of other tyrosine kinase receptors. Moreover, some mutations in the EGFR receptor kinase domain seem to play a crucial role in determining the sensitivity of cancer cells to specific inhibitors by altering the conformation of the receptor and its activity. The development of rational combinations of anticancer agents and EGFR inhibitors, able to exert synergistic cytotoxic interactions, has been widely accepted and used in both preclinical and clinical studies. Although the failure of large clinical trial based on empirical combination of anti-EGFR and classic chemotherapeutic agents, several preclinical data seems to support the hypothesis that combining EGFR inhibitors and other novel agents could efficiently inhibit tumor growth and overcome intrinsic resistance to a single-agent based therapy. This review focuses on the role of complementary signalling pathways in the development of resistance to EGFR targeting agents and the rationale to combine novel inhibitors as anticancer therapy.

Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered intracellular processes including cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. Metabolites from these processes result in significant cellular oxidative stress that must be buffered to prevent permanent cell damage and cell death. Tumor cells depend on a complex set of respiratory pathways to generate the necessary energy as well as redox-sensitive pro-survival signaling pathways and factors to cope with and defend against the detrimental effects of oxidative stress. It has been hypothesized that redox-sensitive signaling factors such as thioredoxin reductase-1 (TR) and thioredoxin (TRX) may represent central pro-survival factors that would allow tumor cells to evade the damaging and potentially cytotoxic effects of endogenous and exogenous agents that induce oxidative stress. The overarching theme of this review is an extension of the hypothesis that tumor cells use these redox sensitive pro-survival signaling pathways/factors, which are up-regulated due to increased tumor cell respiration, to evade the cytotoxic effects of anticancer agents. These observations suggest that redox-sensitive signaling factors may be potential novel molecular targets for drug discovery.

The short chain fatty acid valproic acid (VPA, 2-propylpetanoic acid) is approved for the treatment of epilepsia, bipolar disorders and migraine and clinically used for schizophrenia. In 1999, the first clinical anti-cancer trial using VPA was initiated. Currently, VPA is examined in numerous clinical trials for different leukaemias and solid tumour entities. In addition to clinical assessment, the experimental examination of VPA as anti-cancer drug is ongoing and many questions remain unanswered. Although other mechanisms may also contribute to VPA-induced anti-cancer effects, inhibition of histone deacetylases appears to play a central role. This review focuses on recent developments regarding the anti-cancer activity of VPA.

Chemoprevention is one of the most important strategy in the field of cancer control. Molecular mechanism-based cancer chemoprevention by phytochemicals seems to be very attractive method. In this review, possible molecular targets for cancer prevention are overviewed, and some examples of cancer preventive phytochemicals, such as carotenoids, are presented.

Nuclear factor-κB (NF-κB) is a transcription factor that is activated in response to various inflammatory stimuli such as cytokines, growth factors, hormones, mitogens, carcinogens, chemotherapeutic agents, viral products, eukaryotic parasites, endotoxin, fatty acids, metals, radiation, hypoxia, and psychological, physical, oxidative, and chemical stresses. In addition, constitutively active NF-κB is frequently encountered in a wide variety of tumors. Furthermore, NF-κB activation has been shown to regulate the expression of over 400 genes involved in cellular transformation, proliferation, inflammation, viral replication, antiapoptosis, angiogenesis, invasion and metastasis, oxidative stress, and osteoclastogenesis. Therefore, because of the critical role NF-κB plays in the pathogenesis of cancer, specific inhibitors of this factor are being sought. Agents that prevent cancer or inflammation have been found to suppress NF-κB activation. Numerous reports indicate that ancient plants and their components are potent as NF-κB inibitors. However, ancient medicine such as traditional Chinese medicine, Kampo, Ayurveda requires rediscovery in light of our current knowledge of allopathic (modern) medicine for the therapeutic and preventive purpose. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with NF-κB pathway. The structure of drugs and their relationship with NF-κB inhibitory activity is discussed.

There is an immense diversity of marine plants and animals from which an estimated 14,000 pharmacologically active compounds have been isolated. However, in terms of clinically useful anti-cancer agents, the oceans remain as a largely untapped resource. Indeed, there are currently only two compounds used in the clinic that are derived from marine sources. These are cytarabine, which is a deoxycitidine analogue and aplidine, which has both growth inhibitory and anti-angiogenic effects. This situation is likely to change rather dramatically in the near future, as attention has focused on the vast diversity of available agents from marine organisms. The increased pace of activity in this area has resulted in a several clinical trials of promising compounds with the probability that these will be followed by other drugs currently under preclinical development.

The marine ecosystem that has contributed to the discovery of cytarabine and its fluorinated derivative gemcitabine is now considered the most productive toll to acquire new natural derived anticancer entities. Few marine anticancer agents have entered clinical development, including bryostatin-1, dolastatin 10, LU103793, ET-743, kahalalide F, didemnin B and aplidine. The marine plitidepsin aplidine derived from the mediterranean tunicate Aplidium albicans is a synthetically produced anticancer agent that is structurally related to didemnins. Aplidine's mechanism of action involves several pathways, including cell cycle arrest, inhibition of protein synthesis and antiangiogenic activity. Phase I studies have been reported for a number of several schedules including 1-hour, 3-hour and 24-hour infusion. Evidences of antitumor activity and clinical benefit of aplidine in several tumor types were noted across phase I trials, particularly in advanced medullar thyroid carcinoma. Phase II studies are underway. Within the entire phase I program, dose-limiting toxicities of aplidine were neuromuscular toxicity, asthenia, skin toxicity, and diarrhea. Interestingly, no hematological toxicity was observed. Aplidine displayed a very peculiar delayed neuromuscular toxicity that was found to be closely related to the symptoms described in the adult form of carnitine palmitoyl transferase deficiency type 2, which is a genetic disease treated with L-carnitine. Consistently, concomitant administration of L-carnitine allowed to improve aplidine-induce neuromuscular toxicity. In summary, aplidine is a novel marine anticancer agent with a very particular delayed neuromuscular toxicity that requires careful follow- up with promising antitumor activity.

Tumor cells are not only susceptible to signals from the environment, but they likewise release signal substances. It is well known that tumor cells secrete angiogenic factors - most prominently the vascular endothelial growth factor - which initiate the vascularization of the tumor for its nourishment. This process has been termed neoangiogenesis. Besides this, two further processes have recently been discovered that facilitate the interaction of the tumor with the lymphatic system and the nervous system, named lymphangiogenesis and neoneurogenesis. These three “geneses” have a cognate, in part common regulation and conjointly promote metastasis development. Neoangiogenesis and lymphangiogenesis provide the structures for the two routes of tumor cell dissemination, i.e. either hematogenous or lymphatic. Neoneurogenesis accomplishes the innervation of the tumor by the ingrowth of nerve endings into the tumor and alternatively or additionally by the protection of existing nerve cells from destruction. These tumor-innervating nerve cells may release neurotransmitters which are proliferative or promigratory signals for the tumor cells. Furthermore, nerve fibers are used as routes for tumor cell dissemination, too, which is known as perineural invasion.

Cyclosarin is one member of nerve agent family. Recent treatment of intoxications by organophosphorus compounds, such as nerve agents or pesticides, consists of rapid administration of anticholinergics and AChE reactivators. Owing to the threat of terroristic use of these compounds during last years, improvement of antidotal therapy still continues. As the part of the development of new antidotes, many new AChE reactivators were synthesized and currently some of them are under consideration for introducing them to the medical practice. Their biological activity depends, as in the case of other drugs, on their chemical structure, which affects their pharmacokinetics (adsorption, distribution, metabolism and excretion) and pharmacodynamics. In this review, we would like to discuss relationship between structure of currently available AChE reactivators and their potency to reactivate cyclosarin-inhibited AChE. All outlined structural factors presented in this work should be helpful for the design of new generation of reactivators of cyclosarin-inhibited AChE.