Current Pharmaceutical Design - Volume 15, Issue 7, 2009

While cancer remains a major killer in the developed world, a broad spectrum of novel and exciting approaches are being developed and tested. This issue of Current Pharmaceutical Design “Anti-cancer drugs” will once again highlight several of these developments and present an up-to date overview. Among the molecules used or targeted in the research described are both novel compounds with promising activity such as the Prodigiosins, and familiar molecules whose function and involvement in tumorigenesis have only recently been appreciated, such as the key role that chemokines play in metastasis. A common theme, however, is the increasing selectivity of the pathways that are being targeted resulting in more and more selective anti-tumor activity and ever decreasing off-target effects. Another highly encouraging aspect is the effectiveness of some approaches, such as the use of novel NF-κB inhibitors, on tumors which have developed resistance to a broad spectrum of conventional chemotherapeutics or immunotherapy. Pandey et al. review the bacterial pigment family of Prodigiosins, which contain compounds with strong antimicrobial, anti-malarial and anti-neoplastic activity [1]. While the mode of action is not completely defined, several signaling pathways seem to be involved in the mediation of anti-cancer activities and the authors summarize the latest findings in regards to the mechanisms. Wu et al. first provide us with an overview over chemokines and their receptors and then report on the latest advances in targeting chemokine receptors for cancer therapy [2] as the involvement of these molecules in metastasis is slowly being unveiled. Another novel set of weapons in the fight against cancer cells are receptor tyrosine kinase (RTK) inhibitors which are reviewed by Sharma et al. [3]. The rationale behind this strategy is that RTKs mediate cell growth by various pathways and are often involved in the initiation and progression of tumors. Inhibitors of these enzymes have shown to revert the malignant phenotype and thus have validated this treatment approach. Inhibitors of RTK can be various classes of molecules, some derived from natural ingredients. Others can be engineered in the form of monoclonal antibodies specific for a particular RTK.

Prodigiosins are a family of bright red colored bacterial pigment and derive their name from the miraculous (prodigious) events associated with their occurrence. They indeed seem to be living upto their name as a host of activities such as anti-microbial, anti-malarial, anti-cancer and immunosuppressive have been associated with them. Out of these, immunosuppressive and anti-cancer activity has received more importance as it has a clinical promise. Prodigiosins, isolated mostly from Gram negative bacteria are characterized by a common pyrryldipyrrylmethene structure with varying side chains. The review discusses the mechanisms involved in the anti-cancer activity of this class of compounds. In vitro, prodigiosins have been shown to primarily target the cancer cells independently of the p53 status while little or no effect has been observed on normal cells. In addition, prodigiosins are effective in cancer cells with multidrug resistance phenotype and defects in the apoptotic pathways. These make prodigiosins attractive candidates for further development. Though the molecular targets of prodigiosins have not been clearly defined, they have been found to target different signaling pathways possibly through induction of DNA double strand breaks and/ or neutralization of pH gradients leading to changes in cell cycle proteins and apoptosis. The review will discuss the recent findings related to the mechanism involved in the anti-cancer activity of this class of molecules.

Chemokines and their receptors play critical roles in leukocyte trafficking during inflammatory processes. Although the role of chemokine receptors (CKRs) in cancer biology is a relatively new field of study, a growing body of data suggest that a number of CKRs, including CXCR4, CCR4, CCR7, and CCR10, may play diverse of roles in cancer growth, cancer metastasis, cancer angiogenesis, or the composition of the cancer microenvironment. Preclinical models of cancer indicate that cancer antagonists, most notably those for CXCR4, can block cancer growth either directly or by altering the cancer stroma. Highthroughput screening methods to identify effective CKR antagonists have been developed, but specificity, potency, and drug-delivery of validated candidate compounds remain issues that result in the clinical failure of many initially promising candidates. The recent approval of a CCR5 receptor antagonist in HIV suggests that safe, effective small molecular antagonists for other CKRs may not be far away. There is still a clear need to extend our understanding of the signalling pathways by which CKRs facilitate cancer processes. Because of the role of CKRs in cancer cell survival, the combination of CKR antagonists with traditional chemotoxic agents or with immunotherapy is an alluring strategy since this increases the specificity of treatment to the cancer and potentially limits additional systemic side effects.

Receptor Tyrosine Kinases class I (RTK class I, EGF receptor family) constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. Activation of EGFR may be because of overexpression, mutations resulting in constitutive activation, or autocrine expression of ligand. In contrast, activation of HER2 occurs mainly by overexpression, which leads to spontaneous homodimerization and activation of downstream signaling events in a ligandindependent manner. EGFR and HER2 have now been validated as a clinically relevant target, and several different types of agents inhibiting these receptors are currently in development. The EGFR inhibitors Erlotinib, Gefitinib, and Cetuximab have undergone extensive clinical testing and have established clinical activity in non small cell lung cancer (NSCLS) and other types of solid tumors. Several of the other erbB inhibitors are also undergoing advanced clinical testing, either alone or in combination with other agents. This review reports various inhibitors, natural, small molecules and monoclonal antibodies, along with their reported activities for various members of erbB family. It will highlight the potential for the development of novel anti-cancer molecules.

The development of metal complexes with anticancer activity has had an enormous impact on cancer chemotherapy. The discovery of cisplatin in the 1960's represented a landmark achievement and ushered in a new era in cancer treatment. Despite the fact that cisplatin has achieved significant clinical benefit for several types of solid tumors, its effectiveness has been hampered by toxic side effects and tumor resistance that often leads to the occurrence of secondary malignancies. However, discovery and use of cisplatin have encouraged investigators to search for and develop novel non platinum-containing metal species with superior anti-cancer activity and low side effects. As examples, gallium salts and gold complexes have been evaluated in phase I and phase II trials. Copper-chelating compounds have also shown promising results in both preclinical and clinical studies. This review provides a comprehensive overview of various non platinum metal complexes and metal-chelating compounds and discusses their potential molecular targets in tumor cells and their applications in cancer therapy.

Tumors develop resistance to cytotoxic apoptotic stimuli induced by various chemotherapeutic drugs and immunotherapies. Therefore, there is a need to overcome chemo- and immuno-resistance of tumors through the development of small molecules, as sensitizing agents, aimed at targeting gene products that regulate the apoptotic pathways and allow therapeutics to be effective. The constitutively activated NF-κB (nuclear factor kappa B) signaling pathway is involved in cell survival, inflammation and metastasis and is invariably constitutively activated in most cancers. Consequently, NF-κB is intimately involved in the regulation of resistance to cytotoxic drugs. A novel NF-κB inhibitor, DHMEQ (dehydroxymethylepoxyquinomicin), inhibits the translocation of NF-κB into the nucleus as well as inhibits DNA binding of NF-κB components and was shown to be a potent chemo- and immuno-sensitizing agent and in combination with cytotoxic therapeutics resulted in significant reversal of resistance and tumor cell death. This review will present various lines of evidence supporting the therapeutic efficacy of DHMEQ when used in combination with conventional/new cytotoxic drugs in the treatment of resistant tumor cells as well as in the prevention of metastasis.

In recent years, complexes formed from a cytokine and antibodies against that respective cytokine (cytokine/ Ab complex) have been shown to induce remarkable powerful changes in the immune system. Strong interest exists especially for complexes formed with Interleukin (IL)-2 and anti-IL-2-antibody (IL-2/Ab complex). IL-2/Ab complex activates maturation and proliferation in CD8+ T cells and natural killer (NK) cells to a much higher degree than conventional IL-2 therapy. In addition, IL-2/Ab complex does not stimulate regulatory T cells as much as IL-2 alone. This suggests the possibility to replace the conventional IL-2 therapy with a therapy using low-dose IL-2/Ab complex. Further synthetic cytokine/Ab complexes are studied currently, including IL-3/Ab complex for its effects on the mast cell population, and IL-4/Ab complex and IL-7/Ab complex for inducing B and T cell expansion and maturation. Cytokine complexes can also be made from a cytokine and its soluble receptor. Pre-association of IL-15 with soluble IL-15 receptor α produces a complex with strong agonistic functions that lead to an expansion of CD8+ T cells and NK cells. However, cytokine/ Ab complexes also occur naturally in humans. A multitude of auto-antibodies to cytokines are found in human sera, and many of these auto-antibodies build cytokine/Ab complexes. This review presents naturally occurring autoantibodies to cytokines and cytokine/Ab complexes in health and disease. It further summarizes recent research on synthetic cytokine/Ab complexes with a focus on the basic mechanisms behind the function of cytokine/Ab complexes.