Current Cancer Drug Targets - Volume 11, Issue 2, 2011

This is the special issue of Current Cancer Drug Targets with emphasis on “Novel Agents for Cancer Chemo-Therapy”. The papers were submitted from all over the world including USA, Europe and Asia. This is one of the current areas of research in cancer treatment, which started during the last decade and, hence, only a few Scientists are working in it. Eight articles were accepted for publication because the contents of these describe the state-of-the-art of cancer treatment by nanoparticles-based anti-cancer drugs including drug delivery through hyperthermia for tumor-targeted therapy. Nanoparticles also have the potential to play key roles in the diagnosis and imaging of brain tumors by revolutionizing both preoperative and intraoperative brain tumor delineation. This allows early detection of pre-cancerous cells, and provides real-time, longitudinal, non-invasive monitoring/ imaging of the effects of treatment. The development of nanoparticles-based anti-cancer drugs seems to be effective, providing low side effects and targeted action on only cancer cells. The most commonly used and future nanoparticles are dendrimers, polymers, liposomes, micelles, inorganic (magnetic iron oxide nanoparticles, silica etc.), organic nanoparticles etc. It has been observed that dendrimers have a bright future in this area for proper imaging, diagnostics, with multi-functional nanoparticulate systems combining targeting and therapy. Recently, molecular targeting of liposome to the lymphatic system may enhance therapeutic efficacy by improvement of initial lymphatic uptake and lymph node retention of liposomes such as ligand receptor and antibody binding on the surface of liposomes. The important molecules used for preparation of nano-drugs include cisplatin, carboplatin, bleomycin, 5-fluorouracil, doxorubicin, dactinomycin, 6-mercaptopurine, paclitaxel, topotecan, vinblastin, etoposide. The mechanisms of nanoparticles-based anti-cancer drugs have not been fully elucidated. Major challenges for applying therapeutic nanoparticles (TNPs) in the clinic are to understand precisely how chemotherapeutic agents are released from TNPs and delivered to the targeted tumor tissues/cells, and how the TNPs' biodistribution affects toxicity in major organs. However, attempts have been made to discuss the exploration of these unresolved issues with comparisons between free drugs and therapeutic TNPs and targeted and non-targeted TNPs. Of course, nanoparticles-based anti-cancer drugs may be the choice of future therapeutics but they have certain side effects and toxicities. This aspect has also been discussed in this issue so that the ongoing research can consider them and try to avoid or remove them in the future. Adverse effects of nanoparticles on human health depend on individual factors such as genetics and existing disease, as well as exposure, and nanoparticle chemistry, size, shape, charges, agglomeration state and electromagnetic properties. Briefly, these drugs have many beneficial properties such as targeted drug delivery and gene therapy modalities. I believe that nano-anti-cancer drugs may be magic bullet drugs for cancer treatment leading to a bright future for cancer therapeutics world wide.

For the last one decade, scientists are working at developing nano anti-cancer drugs with the claim of ideal ones due to their targeted chemotherapic nature. These drugs have many beneficial properties such as targeted drug delivery and gene therapy modalities with minimum side effects. This article describes pros and cons and future perspectives of nano anti-cancer drugs. Efforts have been made to address the importance, special features, toxicities (general, blood identities, immune system and environmental) and future perspectives of nano anti-cancer drugs. It was concluded that nano anti-cancer drugs may be magic bullet drugs for cancer treatments leading to a bright future of the whole world.

In spite of some medications, millions of people are dying every year due to cancer. Additionally, the survival patients suffer from various serious side effects due to the use of available anti-neoplastic medicines. The development of nanoparticle based drugs seems to be effective providing low side effects and targeted action on cancer cells. The present article describes the state-of-the-art of nano drugs in cancer chemotherapy. The nano drugs are target selective and specific towards tumors only resulting into better treatment. The important molecules used for preparation nano drugs are cisplatin, carboplatin, bleomycin, 5-fluorouracil, doxorubicin, dactinomycin, 6-mercaptopurine, paclitaxel, topotecan, vinblastin and etoposide etc. The most commonly used materials for nanoparticle carriers are dendrimers, polymers, liposomes, micelles, inorganic, organic nanoparticles etc. A survey was carried out on the drugs available in the market and given in tabular form. However, the commonly used nano drugs till date are liposome dendrimer and some other materials based on nanoparticles. Attempts have been made to explain the mechanism of action of nano drugs. The future perspectives have also been highlighted in the conclusion part.

Conventional liposomal drug delivery has been associated with obvious limitations, such as a rapid absorption by the recticulo-endothelial system in the liver and spleen, a short circulation time and a low therapeutic efficacy. Various modifications of liposomal drugs have been developed to prolong the duration of actions of the drugs at target sites, reduce its adverse effects and increase therapeutic index of drugs such as polymeric conjugation and polymeric fixation on the surface of a liposome. The lymphatic system is an important highway to spread the metastasis of most human cancers including breast, colon, and lung, ovarian and prostate. To eradicate those metastatic cancer cells from the lymphatic system, several efforts have been made to develop new and efficient lymphatic targeting drug delivery systems in order to achieve a high initial lymphatic uptake and lymph node localization. Recently, molecule targeting of liposome to lymphatic system may enhance therapeutic efficacy by improving the initial lymphatic uptake and the lymph nodal retention of liposomes such as the ligand-receptor and antibodies binding on the surface of liposome. This article aims to review the emerging liposomal drug, which is targeting the lymphatic system. The significant factors associated with targeting liposomal drugs will also be discussed in more detail in this review.

The application of nanotechnology to biomedical research is expected to have a major impact leading to the development of new types of diagnostic and therapeutic tools. One focus in nanobiotechnology is to develop safe and efficient drug/gene delivery vehicles. Research into the rational delivery and targeting of pharmaceutical, therapeutic and diagnostic agents is at the forefront of projects in nanomedicine. Silica, as a major and natural component of sand and glass, is a versatile material due to the variety of available chemical and physical modifications that are available, and recently have been widely applied in nanobiotechnology as drug/gene carriers or fluorescent nano-probes. The goal of this brief review is to illustrate selected examples of various functionalized silica nanoparticles as drug/gene delivery systems that have been applied to the arenas of human disease therapy or detection (molecular and cellular imaging).

This review presents some common features of nanoparticles - activity, toxicity and biological activity. Humans are exposed to tiny particles via dust storms, volcanic ash, and other natural processes and the body systems are well adapted to protect from these potentially harmful intruders. Technological advancement has also changed the character of particulate pollution, increasing the proportion of nanometer-sized particles - “nanoparticles” and expanding the variety of chemical compositions. Studies have shown a strong correlation between particulate air pollution levels, respiratory and cardiovascular diseases, various cancers, and mortality. Adverse effects of nanoparticles on human health depend on individual factors such as genetics and existing disease, as well as exposure, and nanoparticle chemistry, size, shape, agglomeration state, and electromagnetic properties. The key to understand the toxicity of nanoparticles is their size, smaller than cells and cellular organelles, which allows them to penetrate these basic biological structures, disrupting their normal function. Examples of toxic effects include tissue inflammation, and altered cellular redox balance toward oxidation, causing abnormal function or cell death. Some of these materials have desirable characteristics for industrial applications, as nanostructured materials often exhibit beneficial properties, from UV absorbance in sunscreen to oil-less lubrication of motors. In the sense of the huge surrounding positive and negative influence of known and unknown NP-impacts it seems very important to understand and forecast the processes in the body, due to the interaction between these two sides - organism. How nanoparticles can be used as drug delivery systems and imaging devices to increase the efficacy per dose of therapeutic or imaging contrast agents; how nanoparticles will be further developed to improve their functionality in cancer treatment and imaging? How reacts the immune system of the organism after introducing nanoparticles with the aim to defeat tumors? Here the aim was to discuss the right and wrong applications of NP and to answer to some of these questions. In the mean time there will appeare much more investigations because of the important application of the NP not only as drug delivery systems, but as diagnostics as well.

Magnetic nanoparticles have been intensively investigated due to their magnetic characteristics, quantum dot effects, as well as their potential applications in the area of bioscience and medicine. Very promising nanoparticles are magnetic iron oxide nanoparticles with appropriate surface modification which have been widely used experimentally for masses of in vivo applications such as magnetic resonance imaging contrast enhancement, drug delivery, and hyperthermia, etc.. All these biomedical applications require that these nanoparticles have effective magnetic values and suitable sizes. On the other hand, these applications need special surface modification of these particles, which not only have to be non-toxic and biocompatible, but also allow a targetable drug delivery in a specific area. This review summarizes the current research situation and development of magnetic iron oxide nanoparticles, and the biomedical applications ranging from drug delivery to hyperthermia for tumor-targeted therapy.

Despite recent successes, metastatic colorectal cancer remains a difficult cancer to treat. Since the initial discovery that PI-3-Kinase/AKT signaling played an important part in the growth and survival of colorectal tumors, preclinical studies have suggested that inhibitors of this pathway may have a role to play as potential therapeutics. With the surge of inhibitors of PI-3-Kinase from both academia and pharmaceutical companies rapidly moving through early clinical trials, the question of whether these preclinical studies will translate to patients will soon be answered. However, the failure or success of these agents will depend on correctly identifying patients that may benefit, as has been seen with EGFR inhibitors recently approved for treating this disease. Determining the potential of PI-3-Kinase inhibitors in colorectal cancer will depend on factors such as correctly monitoring biomarkers and patient response, enriching clinical trials by proactively stratifying patients into populations based on markers shown to not only predict response to these inhibitors, but also markers which may predict for lack of response, and determining how to combine these inhibitors with both current cytotoxic therapies and approved and emerging targeted therapies with optimal benefit. How these goals may be achieved in the current oncology landscape is addressed in this review with an emphasis on how these agents fit the goal of achieving personalized medicine.

Epigenetic processes play a key regulatory role in cancer. Hypermethylation in the CpG islands of the promoter regions of many tumour suppressor genes leads to the recruitment of co-repressors, altered chromatin structure, and ultimately transcriptional silencing. Key components in the regulation of DNA methylation are DNA methyltransferases (DNMT1, 2, 3A and 3B) and methyl CpG-binding proteins, which recognize methyl cytosine residues and recruit transcriptional repressor complexes, including histone deacetylases (HDAC). DNMT1 is responsible for the maintenance of DNA methylation patterns during replication. Inhibitors of this enzyme may potentially lead to DNA hypomethylation, and re-expression of tumour suppressor genes. Several DNMT inhibitors are currently being evaluated in preclinical and clinical studies, which include various analogues of adenosine, cytidine or deoxycytidine. However, such drugs have had limited clinical success, perhaps because of cytotoxicity associated with their incorporation into DNA. Non-nucleoside small molecule inhibitors of DNMTs can directly block DNMT activity, and may be able to circumvent this cytotoxicity. Post-translational modifications of histones play a key role, not only in regulating chromatin structure and gene expression, but also in genomic stability. Histone acetylation (HAT) and histone deacetylation (HDAC) affect chromatin condensation, with concomitant effects on gene transcription. A further range of compounds is being evaluated for clinical use as HDAC inhibitors, including hydroxamic acids such as Trichostatin A (TSA) and Suberoyl anilide bishydroxamide (SAHA). MicroRNAs are also found to play a key role in cancer development, and novel approaches to their regulation may provide a susceptible anticancer drug target. Because of the interdependence of epigenetic processes, combinations of these approaches may have maximum clinical efficacy.

Previously, we demonstrated that survivin expression is CBP/β-catenin/TCF-dependent. Now, using NCI-H28 cells, which harbor a homozygous deletion of β-catenin, we demonstrate that survivin transcription can similarly be mediated by nuclear γ-catenin. ICG-001, a specific inhibitor of binding to the N-terminus of CBP, effectively attenuates survivin expression. We demonstrate that γ-catenin by binding to TCF family members and specifically recruiting the coactivator CBP drives survivin transcription particularly in β-catenin-deficient cells. We also examined the relative expression of γ-catenin and β-catenin in 90 cases of chronic myeloid leukemia (CML) in a published gene expression microarray data base. A statistically significant negative correlation between γ-catenin and β-catenin was found in AP/BC cases (- 0.389, P = 0.006). Furthermore, in subsequent independent validation studies by qPCR in 28 CP and BC patients increased γ-catenin expression predominated in BC cases and was associated with concomitantly increased survivin expression. Gene expression was 3- and 6-fold greater in BC patients as compared to CP patients, for γ-catenin and survivin, respectively. Consistent with this observation, nuclear γ-catenin accumulation was evident in this population consistent with a potential transcriptional role. Combined treatment with imatinib mesylate (IM) and ICG-001 significantly inhibited colony formation in sorted CD34+ CML progenitors (survivin+/γ-cateninhigh/β-cateninlow) isolated from one BC and one AP patient resistant to IM. Therefore, we believe that the ability of ICG-001 to block both the CBP/γ-catenin interaction and the CBP/β-catenin interaction may have clinical significance in cancers in which γ-catenin plays a significant transcriptional role.

The way cancer cells escape cisplatin-induced apoptosis has not been completely elucidated yet. We questioned the relevance of “metabolic reprogramming” in cisplatin-resistance by studying mitochondrial function and metabolism in human ovarian carcinoma cell lines, cisplatin-sensitive (2008) and -resistant (C13). C13 cells, in comparison to 2008 cells, showed lower apoptotic response to cisplatin exposure, lower basal oxygen consumption (4.2±0.2 vs 6.5±0.7 fmol/cell/min, p< 0.005) and a lower basal transmembrane mitochondrial potential (ΔΨm) (18.7±1.5 vs 32.2±1 MFI p<0.001). Moreover, C13 cells showed a lower sensitivity to rotenone and oligomycin, two mitochondrial respiratory chain inhibitors. To further investigate the impact of mitochondria on cisplatin-resistance, 2008 and C13 cells were depleted of their mitochondrial DNA (rho0-clones). The cytotoxicity of cisplatin was lower in 2008-rho0clones than in 2008 cells (IC50 of 3.56 μM and 0.72 μM, respectively) but similar between C13-rho0 and C13 cells (IC50 of 5.49 μM and 6.49 μM, respectively). The time-course of cell viability in glucose-free galactose medium indicated that C13 cells are more strictly dependent on glucose than 2008 cells. 1H-NMR spectroscopy showed a higher basal content of intracellular glutathione (GSH) and mobile lipids (MLs) in C13 cells as compared to 2008 cells, with higher lipid accumulation mainly within cytoplasmic droplets of the C13 cells. These findings allow us to propose a “metabolic remodelling” of ovarian carcinoma cells to a lipogenic phenotype, which includes alteration of mitochondrial function, as an advantageous mechanism to escape cisplatin-induced apoptosis. This hypothesis is of interest to exploit new pharmacological targets to improve the clinical impact of platinum drugs.