Current Pharmaceutical Design - Volume 16, Issue 1, 2010

The cell death story is still as a current paradigm. Cells may undergo “death” in response to various environmental injuries, or decide to self-destruction in order to ensure proper physiological morphogenesis, preserve tissue homeostasis and eliminate abnormal cells for example in multicellular organisms. Apoptosis and programmed cell death are traditionally used as synonyms and has taken centre stage as the principal mechanism of programmed cell death in mammalian tissues. Programmed cell death should be more accurately defined as cell death that is dependent on genetically encoded signals or activities within the dying cell. In recent years, accumulating evidences suggest that a variety of other molecular cell death pathways have been characterized. Furthermore, the intense focus on apoptosis, and its disturbance in a wide range of human pathologies, perhaps, has blinded us to the significance of these others forms of cell death, and in this special issue “ Molecular mechanisms of cancer cell death” I hope, be useful in putting apoptosis into a broader context. The molecular processes that mediate cell death are more complicated that may have been initially appreciated. Four categories of dynamic cellular activities that lead to cell death have been described: apoptosis, autophagy, necrosis and mitotic catastrophe Permanent growth arrest, known as senescence, is also considered as a type of cell death in the context of cancer therapy [1, 2]. These five cell death class are based on different morphological and biochemical characteristics present in the dying cell. Apoptosis and autophagy have been integrated to be “programmed”, which refers to their strict genetic control. Necrosis and mitotic catastrophe are generally considered passive response to dramatic cellular insult. However, new findings revised in this special issue have demonstrated that these forms of death may also be genetically controlled. Senescence is an essential process of aging and occurs following a gene-direct program involving the erosion of telomeres and the activation of tumor suppression signaling pathway. Acquired defects in signaling pathways that control each of these forms of cell death are among the major hallmarks of cancer. Furthermore, recent evidences suggest that multiple pathways may be activated in single dying cells and cross talk between cell death programs may allow fine control over the ultimate outcome. The inhibition of the dominant molecular route of cell death may not result in survival but, rather, allow the occurrence of alternate programs leading to different types of cell death [3]. Other models of cell death have been described, including caspase-independent apoptosis, necroptosis, paraptosis, pyroptosis, entosis and slow cell death, whose morphologic and biochemical characteristics vary from current definitions of the major cell death pathways describe above [4-6]. In an attempt to simplify this special issue of Current Pharmaceutical Design, only the five best-described cell death outcomes (apoptosis, necrosis, autophagy, mitotic catastrophe and senescence) are presented herein. The whole aim of this special issue is to provide the readers working in basic biomedical sciences and clinicians a comprehensive understanding of different cell deaths involved in human diseases especially neoplastic affections, whose treatment implies the complete understanding of different cell death processes. The first paper by Urriticoechea et al., [7] displayed an overview of recent advances in cancer therapies, focused on to provided the reader to be familiar with the fundamental role of some classic cancer therapies. Following, they focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. The next three papers have dedicated to analyzed deeply the mechanism of apoptosis. Zivny et al. [8] conducted a systematic review of the apoptotic process and its regulation as well as mechanisms of action of conventional anticancer drugs and new promising agents, which trigger directly or indirectly apoptosis of haematological cancer cells. A. Carnero [9] complemented such contribution addressing that the PKB/AKT constitutes an important pathway regulating the signalling of multiple essential biological processes specially those that are able to confer tumorigenic properties in cells. The review's author showed evidences indicating that the AKT pathway is a potential target for cancer chemotherapy. Finally, Hirst and Robson [10] reviewed the role of nitrosative stress as a mediator of apoptosis as well as their implications in cancer treatment.

The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of tumours seem to be the cornerstone of any therapy is now emerging. Here we provide an overview on the different approaches to cancer treatment. This review will help the reader to acknowledge the pivotal role of some classic cancer therapies, including surgery, radiation, chemotherapy and endocrine therapy, now better understood in the mechanims underpinning their efficacy. Following, we focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. We briefly elaborate, finally, on new biomarkers development and how it should rule and determine the future of therapeutic research in cancer.

Apoptosis is a normal aspect of human physiology ensuring tissue homeostasis. Evasion of endogenous cell death processes, including apoptosis, represents one of the characteristics of cancer. Defects in the physiological mechanisms of apoptosis contribute to the pathological cell expansion and to the development and progression of cancer. Resistance of malignant cells to cancer therapeutic agents may be, in some cases, caused by dysregulation of apoptotic pathways, e.g. BCL2 or IAP overexpression. The understanding of the physiological mechanisms that control apoptosis and the elucidation of apoptotic defects in cancer cells may lead to the development of targeted cancer therapies. Apoptotic pathways, molecules involved in the cross-talk between individual apoptosis pathways and promising new anti-cancer agents, which trigger directly or indirectly apoptosis of hematologic cancer cells, are reviewed in this article.

PKB/AKT constitutes an important pathway that regulates the signaling of multiple essential biological processes. PTEN is a dual protein/lipid phosphatase whose main substrate is phosphatidyl-inositol,3,4,5 triphosphate (PIP3), the product of PI3K. Increases in PIP3 result in the recruitment of PDK1 and AKT to the membrane where they are activated. Furthermore, PI3K can be activated by direct binding to oncogenic Ras proteins. Many components of this pathway have been described as genetically altered in cancer. PTEN activity is lost by mutations, deletions or promoter methylation at high frequency in many primary and metastatic human cancers, and some germline mutations of PTEN are found in several familial cancer predisposition syndromes. Activating mutations of PI3K occur in human tumors and confer tumorigenic properties to cells in culture. Taken together, this evidence indicates that the AKT pathway is a promising potential target for cancer chemotherapy. Indeed, many companies and academic laboratories have initiated a variety of approaches to inhibit the pathway at different points. Essentially, PI3Ks, PDK1, AKT and mTOR are heavily targeted for therapy in different ways. These proteins are kinases, which are very “druggable” targets a priori, and, according to the “addiction hypothesis”, cancer cells with the activated pathway will be more dependent on its activity for their survival.

Nitric oxide (NO°) is now recognised as one of the most important molecules influencing the development, progression and treatment of cancer. A key component of its action is as a negative and positive regulator of apoptosis. Broadly, constitutive levels of NO° (nM), are capable of inhibiting numerous signalling pathways in both normal and cancer cells. These include soluble guanylate cyclase, leading to reduced Ca++ signalling, inhibition of caspases and scavenging of reactive oxygen species, all of which promote survival signalling. High concentrations (μM-mM) on the other hand, generally promote apoptosis. Pathways involving cGMP, cytochrome c release, mitogen activated kinases, ceramide and poly(ADP)ribose polymerase have all been implicated. The role of p53 in NO°-induced cell death has been widely studied. In many cell types p53-dependent signalling is involved, while in others, apoptosis occurs in the absence of functional p53. There is also evidence that the tumour microenvironment, where low oxygen and glucose levels prevail, enhances cell death signalling by NO° and peroxynitrite, thus tumours may be more sensitive to high levels of NO° than their normal tissue counterpart. The cytotoxicity of NO° has been studied directly in many tumour models, both in vitro and in vivo. In all cases, high concentrations of NO°, generated by donor drugs or by iNOS gene transfer caused extensive tumour cell death, which was enhanced by the ability of NO° to diffuse readily from its source of generation to most cells within tumours. NO° was also a very effective enhancer of conventional chemo- and radiotherapy. Thus, NO° therapy has great potential to improve the treatment of cancer.

Until recently, necrosis, unlike apoptosis, was considered as passive and unregulated form of cell death. However, during the last decade a number of experimental data demonstrated that, except under extreme conditions, necrosis may be a well-regulated process activated by rather specific physiological and pathological stimuli. In this review, we consider mechanisms and the role of necrosis in tumor cells. It became recently clear that the major player in necrotic cascade is a protein kinase RIP1, which can be activated by number of stumuli including TNF, TRAIL, and LPS, oxidative stress, or DNA damage (via poly-ADP-ribose polymerase). RIP1 kinase directly (or indirectly via another kinase JNK) transduces signal to mitochondria and causes specific damage (mitochondrial permeability transition). Mitochondrial collapse activates various proteases (e.g., calpains, cathepsin) and phospholipases, and eventually leads to plasma membrane destruction, a hallmark of necrotic cell death. Necrosis, in contrast to apoptosis, usually evokes powerful inflammatory response, which may participate in tumor regression during anticancer therapy. On the other hand, excessive spontaneous necrosis during tumor development may lead to more aggressive tumors due to stimulatory role of necrosis-induced inflammation on their growth.

Mitotic catastrophe is a mechanism of cell death characterized by the occurrence of aberrant mitosis with the formation of large cells that contain multiple nuclei, which are morphologically distinguishable from apoptotic cells. Sometimes, mitotic catastrophe is used restrictively to indicate a type of cell death that occurs during or after a faulty mitosis leading to cell death, which takes place via necrosis or apoptosis, rather than a cell death itself. Several antitumor drugs and ionizing radiation are known to induce mitotic catastrophe, but precisely how the ensuring lethality is regulated or what signals are involved is barely characterized. The type of cell death resulting from antitumor therapy can be determined by the mechanism of action of the antitumor agent, dosing regimen of the therapy, and the genetic background in the cells being treated. Wild-type p53 promotes apoptosis or senescence, while mitotic catastrophe is independent of p53. Mitotic catastrophe can be regarded as a delayed response of p53-mutant tumors that are resistant to some damage. In this context, the elucidation of the mechanisms of treatment-induced mitotic catastrophe should contribute to an improvement of the antitumor therapy, because most of the solid tumors bear an inactive p53 protein.

Senescence is defined as an irreversible growth arrest that is characterised by a changed morphology, gene expression pattern and chromatin structure as well as an activated DNA damage response. Senescence has a dual role for tumour development. Firstly, it acts as a tumour suppressor to prevent the proliferation of seriously damaged cells. Important mechanisms ensuring the stop of genomically altered cells to proliferate are the activation of ATM, p53 and the DNA damage response (DDR). In addition it emerges in recent years that oncogene activation acts as a genetic stress and induces senescence as well using similar downstream components: DNA damage activation, changes in gene expression and chromatin structure. Therefore, senescence functions as a powerful tumour suppressor that protects cells expressing activated oncogenes in vivo from becoming neoplastic and malignant. The fact, that oncogene induced senescent cells were mainly found in early, pre-malignant tumour stages suggest that this senescent state has to be overcome during tumourigenesis in order for a tumour to progress to malignancy. At the same time cellular senescence is increasingly recognised as a possible outcome for the treatment of human tumours because it is executed by cells in response to therapeutic treatments, such as drugs and irradiation. While historically apoptosis was considered the only desirable outcome of any anti-neoplastic treatment it emerges recently that senescence could be a potential alternative outcome for tumour therapy in vivo. Animal and tissue culture models have been developed over the last years shedding more light on this novel field of cancer treatment. Whether senescence induction is an advantage or a backdrop for tumour treatment has still to be elucidated since experimental proof in human tumour models is still in an infant stage. This review focuses on the basic mechanisms and recent advances for the induction of senescence as a potential outcome of cancer therapy and discusses the potential for a clinical application.

Autophagy is an evolutionarily conserved degradation pathway which primary functions as a cell survival adaptive mechanism during stress conditions. Autophagy is a tumor suppressor process and induction of the autophagic machinery can cause cell demise in apoptosis-resistant cancer. Thus, this metabolic pathway can act either to prevent or to promote carcinogenesis, as well as to modulate the response to anticancer therapies, included drug-induced apoptosis. Conventional therapies exert their cytotoxic activity mainly by inducing apoptosis. Massive activation of the apoptotic program in a tissue can result in cell loss providing a selective advantage for growth to displastic cells and tumor cell subpopulations with high levels of malignancy. This suggests that the activation of autophagy can counteract malignancy. On the contrary, therapeutic intervention-induced apoptosis can eliminate cells with pro-mutational biochemical alterations at risk for initiation, initiated cells and cells of focal and advanced preneoplastic and neoplastic lesions. Thus, pharmacological inhibition of autophagy may enhance apoptosis. Autophagy and apoptosis share common stimuli and signalling pathways, so that the final fate, life or death, depends on the cell response. Recently, accumulating data fuel novel potential therapeutic interventions to modulate autophagy to be beneficial in cancer therapy. This review highlights current knowledges aimed at unraveling the molecular interplay between autophagy and cell death as well as the possible therapeutic exploitation in cancer.

Aberrantly regulated apoptosis is involved in the pathogenesis of several diseases and defective apoptosis leads to uncontrolled cell proliferation and tumorigenesis. Cancer is an example of a pathologic condition where the normal mechanisms of cell cycle regulation are dysfunctional either by excessive cell proliferation, inhibited/suppressed apoptosis or both. Dietary habits are estimated to contribute to, at least, one third of all human cancers, showing that dietary components can exacerbate or interfere with carcinogenesis. However, several epidemiological studies have revealed that some dietary factors can decrease the risk of different types of cancer. Apoptosis is suggested to be a crucial mechanism for the chemopreventive properties associated with several dietary factors by eliminating potentially deleterious (damaged/mutated) cells. Food, a readily available item, contains several promising chemopreventive agents. Polyphenols are serious candidates since they are responsible for the cancer protective properties of a diet rich in vegetables and fruits: numerous phenolic compounds showed antiproliferative and cytotoxic effects and, more specifically, pro-apoptotic activities, in several cancer cells lines and animal tumor models. The aim of the present review is to analyze and summarize several aspects related to the molecular mechanisms of apoptosis induced by dietary factors with particular emphasis on polyphenols. Dietary factors that can activate cell death signals and induce apoptosis, preferentially in precancerous or malignant cells, and the study of their apoptotic inducing targets can represent a mean to devise new strategies for cancer prevention in the future.