Current Drug Targets - Volume 11, Issue 6, 2010

The term of apoptosis was introduced in 1972 by Kerr et al. to describe a genetically programmed cellular process of cell dearth [1], which forms an integral part of the life cycle of higher organism. Nearly 40 years later, apoptosis has been regarded as a primary cause or a secondary effect in various diseases including cancers, and has appeared to be a very productive “factory” for the development of new therapeutics. Chemotherapy is the mainstay of cancer treatment. Most, if not all, chemotherapeutic agents kill cancer cells by targeting one or more key apoptotic molecules. However, cancer cells frequently develop different mechanisms to evade apoptosis, making them insensitive to chemotherapeutic agents [2,3]. In order to overcome the chemoresistance, we have to understand how apoptotic pathways are executed in cancer cells, and to generate novel chemotherapeutic agents/protocols that can significantly and specifically induce apoptosis in cancer cells. There are a burgeoning number of studies on the development of new anti-tumor agents that target apoptotic molecules. However, articles that systemically summarize these new developments somehow do not get timely update. According to the available information from Pubmed, the most recent review papers on apoptosis and chemotherapy were published around 3-4 years ago. In this special issue of Current Drug Targets, entitled “apoptosis and chemotherapy”, seven review articles are focused on different aspects of chemotherapy and apoptosis. Ahmad et al. excellently review the modulatory effects of cruciferous vegetable-derived indole compounds, particularly indole-3-carbinol and its dimeric product, 3, 3' diindolylmethane, on apoptotic-related molecules such as survivin, uPA/uPAR and NF-κB. The convincing evidence supports that the chemosensitizing properties of these indole compounds are achieved by inducing apoptosis. In addition to vegetables, potential chemotherapeutic agents have also been discovered in a variety of other sources. The development of the marine organismderived apoptosis-inducing compounds that possess chemotherapeutic property is still in its neonatal age. The article by Lin et al. evidently shows the great potential in this novel area by reviewing apoptosis-inducing and anticancer activities of several compounds isolated from marine organisms. Yang and Dou nicely summarize molecular targets and biological properties of terpenoids that are a group of natural compounds found in a variety of fruits, vegetables and medicinal plants. Some of the terpenoids are able to induce tumor cell death by inhibiting multiple cancer-specific targets including the proteasome, NF-κB, and Bcl-2. Due to the fact that some of the terpenoids are structurally similar to human hormones, these terpenoids appear to be particularly applicable for hormone-related tumors such as breast and prostate cancers. Article by Chung and Irwin provides valuable insights into how targeting multiple members of the family of p53 proteins including p53, p63, and p73 can greatly enhance the inhibition of cancer cell growth. The regulatory pathways controlling the p53-family proteins contribute to the apoptosis in a variety of cancer cells. Understanding these regulatory pathways will indubitably benefit the development of novel chemotherapeutic agents. There is a close relationship between gastro-intestinal cancers and epithelial growth factor receptor (EGFR). Kanwar et al. discuss different approaches to change the level of EGFR in gastrointestinal malignancies. These approaches include antibodies, small molecule EGFR tyrosine kinase inhibitors, gene mutations and dietary agents, through which the chemotherapy of gastro-intestinal cancers will be significantly affected. Karnak and Xu analyze the various approaches to modulate Bcl-2 family proteins in prostate cancer. Overexpression of the anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 are often associated with prostate cancer and contribute to chemoresistance. Therapeutic strategies including DNA anti-sense, RNA interference, small molecule inhibitors and peptides have been designed to either limit the source or disrupt the interactions of these pro-survival Bcl-2 family members, therefore resuming or improving the sensitivity of the cancer cells to chemotherapy. Liu et al. systemically describe the recent advances in chemotherapies for thyroid cancer. These treatments target various molecules in the key steps of thyroid carcinogenesis by either enhancing pro-apoptotic molecules or suppressing anti-apoptotic ones. Much of the attention is devoted to the compounds targeting thyroid cancer cells that do not normally respond to traditional therapy. We sincerely hope that this special issue is an important source of information that is useful for anyone interested in the role of apoptosis in chemotherapy and that stimulates the development of novel treatments for cancers.

Indole compounds, obtained from cruciferous vegetables, have been investigated for their putative anti-cancer properties. Studies with indole-3-carbinol (I3C) and its dimeric product, 3, 3'-diindolylmethane (DIM), have indicated efficacy of these compounds against a number of human cancers. Available as well as emerging data suggests that these compounds act on a number of cellular signaling pathways leading to their observed biological effects. Such pleiotropic effects of these compounds are also considered crucial for their chemosensitization activity wherein they help reduce the toxicity and resistance against conventional chemotherapeutic drugs. These observations have major clinical implications especially in chemotherapy. Through this review, we have attempted to update current understanding on the state of anticancer research involving indole compounds. We have also summarized the available literature on modulatory effects of indoles on molecular targets such as survivin, uPA/uPAR and signaling pathways such as the NF-κB pathway, which are important for the apoptosis-inducing and chemosensitizing properties of these compounds.

The p53-family of transcription factors consists of three genes - p53, p63, and p73 - that share significant structural and functional similarities. Although these genes encode multiple variants that have opposing functions in cancer biology, the full-length, transactivating (TA) p53-family members are potent inducers of apoptosis and tumor suppression. Many anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed small molecules, exert their effects by enhancing the anti-proliferative effects of p53 and TAp63/p73. In this review, we provide an overview of the regulatory pathways controlling the p53-family proteins as a framework for understanding p53-family targeted drug mechanisms. We will also summarize recent work on promising attempts to re-activate p53 in tumors. In addition, we will discuss how p63 and p73 - the two more recently discovered p53-family members - have affected drug discovery and how these two genes may also hold promise as drug targets for recent and future novel therapies. This review will emphasize how targeting multiple members of the family of p53 proteins is likely to provide an increased threat to the growth of cancer cells.

In the past 10 to 15 years, a considerable progress has been made in the treatment of gastrointestinal (GI) related malignancies, as a number of agents expanded from only one in 1995 to seven in 2006. Current review describes the recent role of targeted therapies, specifically EGFR inhibitors in the treatment of GI cancers. Importance of dietary agents in the treatment and prevention of GI cancers is also reviewed.

A major challenge in oncology is the development of chemoresistance. This often occurs as cancer progresses and malignant cells acquire mechanisms to resist insults that would normally induce apoptosis. The onset of androgen independence in advanced prostate cancer is a prime example of this phenomenon. Overexpression of the prosurvival/ anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 are hallmarks of this transition. Here we outline the evolution of therapeutics designed to either limit the source or disrupt the interactions of these pro-survival proteins. By either lessening the stoichiometric abundance of Bcl-2/xL/Mcl-1 in reference to their pro-apoptotic foils or freeing these proapoptotic proteins from their grip, these treatments aim to sensitize cells to chemotherapy by priming cells for death. DNA anti-sense and RNA interference have been effectively employed to decrease Bcl-2 family mRNA and protein levels in cell culture models of advanced prostate cancer. However, clinical studies are lagging due to in vivo delivery challenges. The burgeoning field of nanoparticle delivery holds great promise in helping to overcome the challenge of administering highly labile nucleic acid based therapeutics. On another front, small molecule inhibitors that block the heterodimerization of pro-survival with pro-apoptotic proteins have significant clinical advantages and have advanced farther in clinical trials with promising early results. Most recently, a peptide has been discovered that can convert Bcl-2 from a pro-survival to a pro-apoptotic protein. The future may lie in targeting multiple steps of the apoptotic pathway, including Bcl- 2/xL/Mcl-1, to debilitate the survival capacity of cancer cells and make chemotherapy induced death their only option.

Apoptosis as a form of programmed cell death is a critical defense mechanism against the formation and progression of cancer and exhibits distinct morphological and biochemical traits. In an in vivo situation, apoptosis functions to eliminate potentially deleterious cells without causing such adverse effects as inflammatory response and ensuing scar formation. Therefore, targeting apoptotic pathways becomes an intriguing strategy for the development of chemotherapeutic agents. Marine natural products have become an important source in the discovery of antitumor drugs, especially when modern technology makes it more and more feasible to collect organisms from seas. Although lack of an analog of a long ethno-medical history for finding clues, as compared with terrestrial habitats, still hinders the progress, an increasing number of compounds have been isolated from marine organisms that have been found to possess apoptosis-inducing and anticancer activities. This primer summarizes several such compounds, based on their effects on apoptotic signaling pathways, although most of these products have not yet been studied in depth for their mechanisms of action.

Current therapeutic options for patients with progressive thyroid cancer are relatively ineffective. There is a clear need to develop new alternatives for the management of this malignancy. As the knowledge of thyroid cancer biology advances, a large number of genetic events, molecular abnormalities, alterations of signaling pathways have been identified in the development and progression of thyroid neoplasms, and the potential exists to develop compounds targeted to treat thyroid cancers that do not respond to traditional therapy. In this review we described the recent development in thyroid carcinogenesis where the potential and novel intervention may exist. The discussion of thyroid carcinogenesis was integrated with exploitation of anti-thyroid agents that are currently either in clinical trials or in preclinical development for thyroid cancer.

Terpenoids represent a large and diverse class of naturally occurring compounds found in a variety of fruits, vegetables and medicinal plants. Structurally some of the terpenoids are similar to human hormones. A diet rich in terpenoids is inversely related with the risk of chronic diseases including cancers. Breast and prostate cancers are hormone-related diseases and the second leading cause of female and male cancer mortality. Diterpenoid paclitaxel, and its semi-synthetic analogue docetaxel, have entered clinical use against established breast and prostate cancers. Here we reviewed potential molecular targets and biological properties of natural terpenoids, including monoterpenoids, diterpenoids, triterpenoids and tetraterpenoids, and their applications in treatment of human breast and prostate cancers. These terpenoids are able to inhibit tumor cell proliferation and induce tumor cell death by inhibiting multiple cancerspecific targets including the proteasome, NF-κB, and antiapoptotic protein Bcl-2. The efficacy of these terpenoids against breast or prostate cancer cells, as demonstrated in pre-clinical studies supports clinical application of these naturally occurring terpenoids in treatment of hormone-related human cancers.

The Notch signaling pathway maintains a balance between cell proliferation and apoptosis, and thus it is believed that Notch signaling pathway may play an important role in the development and progression of several malignancies. However, the functions of Notch signaling in EMT are largely unknown. This mini review describes the role of Notch signaling pathway in EMT, and cataloging how its deregulation is involved in EMT and tumor aggressiveness. Further attempts have been made to summarize the role of several chemopreventive agents that could be useful for targeted inactivation of Notch signaling, and thus it may cause reversal of EMT, which could become a novel approach for cancer prevention and treatment.

Pain in patients with impaired renal function may be a significant problem requiring treatment with opioids. However, pharmacokinetic and metabolic changes associated with an impaired renal function may raise some concerns about side effects and overdosing associated with opioid agents in this patient's population. In order to give recommendations on this issue, we review the available evidences on the pharmacokinetics and side effects of most common opioids used to treat pain. The results of this review show that the half-life of the parent opioid compounds and of their metabolites is increased in the presence of renal dysfunction, for which careful monitoring of the patient, dose reduction and a longer time interval between doses are recommended. Among opioids, morphine and codeine used with great caution and possibly avoided in renal failure/dialysis patients; tramadol, hydromorphone and oxycodone can be used with caution and close patient's monitoring, whereas transdermal buprenorphine, methadone and fentanyl/sufentanil appear to be safe to use in patients with renal failure.

Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic-metabolizing enzyme (XME) involved in the biotransformation of many aromatic and heterocyclic amines. This XME plays key roles in both the detoxification and/or bioactivation of numerous drugs and carcinogens. NAT1 is polymorphic and displays a large tissue distribution. NAT1 activity has been extensively studied because of its potential role in the biotransformation of important carcinogens. Several recent studies suggest that NAT1 may have a role in breast cancer progression. Indeed, this XME has been shown to affect the growth and drug resistance of breast cancer cells and appears as a marker in human estrogen receptor positive breast cancer. In addition, it has been shown that this enzyme is inhibited in vivo by cancer drugs such as cisplatin or tamoxifen. Recent published data suggest that NAT1 could be of therapeutic interest for cancer. We provide here an overview on the putative involvement of NAT1 in cancer and its possible role as a drug target.