Anti-Cancer Agents in Medicinal Chemistry - Volume 9, Issue 9, 2009

A number of evidences indicate apoptosis plays an important role in the pathogenesis, etiology, cancers and numerous medical disorders. Molecular imaging of apoptosis may therefore be very useful in clinical practice, assisting in diagnosis, staging and monitoring of disease, monitoring of the course of disease, or assessment of efficacy of the treatment. Several review articles, including the journal papers and books, published within last few years provide good illustration how broad these efforts made [1-7]. However, there are increasing interests and demands for the development of non-invasive imaging methodologies and strategies for the quantification of apoptosis. To quantitatively assess apoptosis would facilitate pre-clinical and clinical evaluation of novel diagnosis and therapeutics. In this regards, to design, evaluate and develop a biomarker for imaging apoptosis with corresponding molecular imaging modality will be of great challenges. Despite both the diagnosis and treatment of varied diseases benefiting from imaging of apoptosis, most new drugs are thought to induce apoptotic tumor cells or their supportive vasculatures. Therefore, imaging agents that can noninvasively monitor apoptosis in response to these new drugs could help streamline the drug development process. The opening paper of this issue by Dr. Blankenberg discusses about the existing imaging agents and modalities that are currently undergoing clinical testing and those that could be rapidly translated into humans. Dr. Cho and coauthors describe the apoptosis mechanisms and altered apoptosis regulators expression and gene mutation in lung cancer. Next three papers discuss the key aspects on the development of probes for molecular imaging of apoptosis. Dr. Aboagye and coauthors summarize the development of new apoptosis detecting probes that have the potential for bridging different stages of the evaluation process. Dr. Faust and coauthors describe recent progresses in tracer development for the molecular imaging techniques PET, SPECT and optical imaging and highlight the discussion of breakthroughs, drawbacks and methodological issues of apoptosis imaging. Dr. Zeng and coauthor concentrate the recent advance of small molecular based probes for detecting apoptosis. Followed by two papers are dealing with imaging apoptosis with Annexin V and its application in preclinical and clinical research. Dr. Wang RF provides the progresses on the studies with Annexin V on preclinical and clinical application in nuclear medicine. Dr. Yuji and coauthors are considering the apoptosis imaging with annexin A5 radio-probes, focusing on its application to the evaluation of the tumor response to chemotherapy. Dr. Wang HW and coauthors provide the updated information in cell death detection using the NADH/FAD fluorescence spectroscopy and imaging based on measurement of the intensity or lifetime of NADH or FAD fluorescence. The last paper of this issue by Dr. Zhao brings tremendous progress which has been made in applying the concept of apoptosis imaging toward diagnostic needs. I believe that this issue will successfully introduce the readers to exciting and challenging area of apoptosis imaging.

There is a rapid expansion in the number of new anti-cancer drugs with remarkably different mechanisms of action that can augment traditional chemotherapy. As these agents are often used in combination with traditional chemotherapy testing the effects of these novel agents has proven difficult requiring large sample sizes to detect relatively small differences in patient survival. Despite the wide variety of mechanisms, most new drugs are thought to ultimately induce apoptosis of tumor cells or their supportive vasculature. Imaging agents that can non-invasively monitor apoptosis in response to these new drugs could therefore help streamline the drug development process. They may also help guide oncologists to identify those patients that could best benefit from a given therapeutic regimen, dose, or duration of drug. In this article we will outline the existing imaging agents and modalities that are currently undergoing clinical testing and those that could be rapidly translated into humans.

Apoptosis is natural process in the development and maintenance of multicellular organisms. However, tumor cells often have faulty apoptotic pathways. The defects of apoptosis are partially caused by mutation and aberrant expression of apoptotic proteins. The apoptosis inactivation is implicated with both tumorigenesis and drug resistance. In addition, as compared to small-cell lung cancers, non-small cell lung cancers are less sensitive to radiation treatment or chemotherapy. Therefore, understanding the mechanisms of apoptosis induction in lung cancer cells is very important for anti-lung cancer drug development and lung cancer therapy. In this review, we discussed about the apoptosis mechanisms and altered apoptosis regulators expression and gene mutation in lung cancer.

Deregulated apoptosis is involved in several diseases including myocardial infarction, ischemia and neurodegenerative disorders, which are characterized by excessive apoptosis. In contrast, resistance to apoptosis is defined as one of the hallmarks of cancer. It therefore follows that strategies that enable the quantitative detection of apoptosis modulation in vivo would be of enormous benefit in the clinic for diagnosis and patient management (evaluation of response to treatment). In addition, such strategies could be used to evaluate the efficacy of novel therapeutics along their development process. During the development of novel therapeutics it would be necessary to evaluate drug efficacy in vitro and then in experimental animal models and, ultimately, in clinical trials. Currently there is no one single probe that is suitable for imaging apoptosis at every stage of evaluation, necessitating a switch between probe types during the development process. This has key implications for the quality and reproducibility of the data obtained. The present review summarizes the development of new apoptosis detecting probes that have the potential for bridging different stages of the evaluation process such that accurate, translational apoptosis imaging data are obtained.

The balance between proliferation and programmed cell death - apoptosis - is essential for multicellular organisms which use apoptosis to regulate and maintain the number and type of their cells during embryogenesis, growth and homeostasis. Increased cell proliferation or enhanced cell loss can be caused by dysregulated apoptosis and are observed in various diseases: in clinical scenarios such as neurodegenerative disorders, myocardial infarction and stroke the rate of apoptosis is upregulated compared to the physiological situation, while in clinical scenarios such as cancer or autoimmune diseases which are connected with pathological proliferation, apoptosis is often downregulated. Therefore, non-invasive imaging of apoptosis is of great clinical interest as patients would clearly benefit from the diagnosis of cell loss post infarction or from monitoring apoptosis triggered by chemotherapy or radiation therapy of tumours. Several biochemical transformations occur in apoptotic cells offering different biological targets for the development of specific molecular biomarkers of apoptosis. Key steps that occur during apoptosis have already been evaluated; among these are the externalisation of phospholipid phosphatidylserine to the outer leaflet of the cell membrane, which can be visualized by labeled annexin A5 and the activation of caspases, especially effector caspase-3, which can be addressed by labeled enzyme substrates or synthetic caspase inhibitors. Here, recent advances in tracer development for the molecular imaging techniques PET, SPECT and optical imaging are presented, the discussion of breakthroughs is involved, drawbacks and methodological issues of apoptosis imaging are highlighted.

Apoptosis, or programmed cell death, is an important physiologic process multicellular organisms use to maintain homeostasis by providing a means for elimination of redundant cells during development. Furthermore, cells that have become damaged or are defective undergo apoptosis to prevent disease. It is an important process involved in the etiology, pathogenesis, and response to therapy of a variety of diseases. Specific biochemical changes occur in cell or tissue undergoing apoptosis that offer potential targets for imaging tracers. There are a number of tracers that can be used to identify apoptotic cells, including morphological changes, caspase activation, and DNA fragmentation. In this article, the recent progresses of small molecular based probes for detecting apoptotic cells are reviewed. In addition, the traditional and modern imaging technologies which use to visualize these probes is also discussed.

The methods of imaging in vivo can depict biological processes at the molecular level. Cell apoptotic imaging belongs to be one of these novel imaging methods. The detection and quantification of apoptosis in vivo are of significant clinical value for diagnosis and assessment of therapeutic efficacy. Here, we focus on discussing the development of apoptosis imaging agents and in vivo studies that have emerged so far, along with their possible applications in nuclear medicine.

Apoptosis, or programmed cell death, is activated in the course of successful anti-neoplastic therapy. Determining baseline levels of apoptosis and the increment of apoptosis induced by therapy can serve as useful prognostic markers. Thus, non-invasive assessment of apoptosis would be desirable to provide clinicians with information on therapeutic efficacy as well as for the development and testing of new anticancer drugs. In these regards, apoptosis detecting radio-probes (radiopharmaceuticals) have been extensively studied. Annexin A5 (annexin V) is an endogenous protein that binds with high affinity and specificity to phosphatidylserine, which is presented on the cell surface in an early process of apoptosis. Accordingly, apoptotic cells can be detected in vivo using annexin A5 labeled with radionuclides, such as 99mTc and 18F. To date, several annexin A5 radio-probes have been developed. Among these, 99mTc- HYNIC-annexin A5 is the best candidate for apoptosis imaging. The apoptosis imaging using radio-labeled annexin A5 has been applied for detecting apoptosis in vivo in the experimental and clinical evaluation of the tumor response to chemotherapy or radiotherapy. The present review describes apoptosis imaging with annexin A5 radio-probes, focusing on its application to the evaluation of the tumor response to chemotherapy. First, principles of apoptosis imaging with annexin A5 radio-probes are described. Next, experimental results with radio-labeled annexin A5 in the evaluation of therapeutic efficacy are discussed. Finally, clinical application of apoptosis imaging with radio-labeled annexin A5 is addressed.

NADH/FAD fluorescence spectroscopy/imaging is an extremely useful tool to probe cellular metabolism and has been applied in the clinic such as early cancer detection. Recently, the potential of using NADH/FAD fluorescence as a biomarker to detect cell death has been investigated for development of cancer treatments with higher efficacy. This review aims to provide the updated information in cell death detection using the NADH/FAD fluorescence spectroscopy and imaging based on measurement of the intensity or lifetime of NADH or FAD fluorescence. The response of NADH fluorescence lifetime to metabolic perturbation, hypoxic environment, and anaerobic glycolysis (e.g., in precancerous tissues and stem cells) is also reviewed to discuss the nature and implications of the lifetime change of NADH fluorescence. Further studies are required to understand the actual site and mechanism of NADH binding of a specific death pathway for future successful in vivo detection of cell death using the NADH fluorescence lifetime.

The noninvasive detection of apoptosis, or programmed cell death, is an important biomarker for the severity/progression of diseases and the efficacy of anticancer therapies. In the past decade a rapid expansion in the number of apoptosis imaging agents and techniques offers an increasingly wide selection of approaches for the assessment of apoptosis in vivo. The goal of this review is to provide a general account of existing and emerging apoptosis imaging techniques based on their modes of actions; and to critically discuss the major advantages and obstacles facing the field of apoptosis imaging. In conclusion, tremendous progress has been made in applying the concept of apoptosis imaging toward diagnostic needs. However, for imaging strategies involving exogenous agents, we must recognize the intrinsic distinction between probe density and target density, and appreciate the complexity of apoptosis imaging within the context of probe behaviors in the target tissue. For non-pharmaceutical imaging strategies, there is a continued drive to improve the specificity and applicability of these endogenous markers. Overall, what remains to be addressed, and is critical to clinical translation, is the noninvasive quantification, in addition to detection, of apoptosis in vivo.

Phosphatidylinositol 3-kinase (PI3K), a heterodimeric lipid kinase, is a key enzyme in signal transduction from various stimuli to downstream pathways that elicit diverse responses involving growth, proliferation, survival, differentiation, and metabolism in many cellular systems. Activated PI3K generates phosphatidylinositol-3,4,5-triphosphate, which recruits phosphatidylinositol-dependent kinase 1 (PDK1) and Akt serine/threonine kinase at the plasma membrane, resulting in activation of Akt. In turn, Akt activates multiple downstream targets, most notably the mTOR pathway. There is abundant evidence implicating the PI3K/Akt/mTOR pathway in the development and progression of a variety of tumors including hematologic neoplasms. Therefore, this pathway is considered a critical target for cancer therapy. We review the regulatory mechanisms of the PI3K/Akt/mTOR signaling pathway and the role of this pathway in oncogenesis of hematological malignancies.